Membrane lipid alterations in the metabolic syndrome and the role of dietary oils

    Membrane lipid alterations in the metabolic syndrome and the role of dietary oils Javier S. Perona PII: DOI: Reference:

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Please cite this article as: Javier S. Perona, Membrane lipid alterations in the metabolic syndrome and the role of dietary oils, BBA - Biomembranes (2017), doi:10.1016/j.bbamem.2017.04.015

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ACCEPTED MANUSCRIPT MEMBRANE LIPID THERAPY

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Membrane lipid alterations in the metabolic syndrome and the role of dietary oils.

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Javier S. Perona

Bioactive Compunds, Nutrition and Health Instituto de la Grasa-CSIC

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Campus Universidad Pablo de Olavide Ctra. Utrera km 1. Building 46

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41013 Seville (Spain)

Abbreviations: apolipoprotein, apo; arachidonic acid, AA; ATP-binding cassette, ABC; body mass index, BMI; c-Jun N-terminal kinase, JNK; chylomicron-like particles, CRLP; diglyceride, DG; docosahexaenoic acid, DHA; eicosapentaenoic acid, EPA; European Prospective Investigation into Cancer and Nutrition, EPIC; extracellular signal-regulated kinase, ERK; fatty acid binding protein, FABP; fatty acid translocase, FAT; fatty acid transport protein, FATP; fatty acid-binding protein fatty acid-binding protein 4, FABP4; glucose transporter, GLUT; homeostasis model assessment of insulin resistance, HOMA-IR; IkB kinase, IKK; insulin receptor substrate, IRS-1; International Diabetes Federation, IDF; lipoprotein lipase, LPL; liver X receptor, LXR; membrane-bound protein kinase C, mPKC; mitogen-activated protein, MAP; monounsaturated fatty acids, MUFA; nonesterified fatty acid, NEFA; peroxisome proliferator-activated receptor-gamma,PPAR-γ; phosphatidyl-ethanolamine, PE; phosphatidylinositol-3 kinase, PI3K; polyunsaturated fatty acids, PUFA; pregnane X receptor, PXR; reactive oxygen species, ROS; saturated fatty acids, SFA; scavenger receptor class B type I, SR-BI; Seguimiento University of Navarra, SUN; TG-rich lipoproteins, TRL; total cholesterol, TC; triglycerides, TG; type-2 diabetes mellitus,T2DM.

ACCEPTED MANUSCRIPT 1. Abstract

The metabolic syndrome is a cluster of pathological conditions, including hypertension, hyperglycemia, hypertriglyceridemia, obesity and low HDL levels that is of great concern

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worldwide, as individuals with metabolic syndrome have an increased risk of type-2 diabetes and

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cardiovascular disease. Insulin resistance, the key feature of the metabolic syndrome, might be at the same time cause and consequence of impaired lipid composition in plasma membranes of insulin-sensitive tissues like liver, muscle and adipose tissue.

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Diet intervention has been proposed as a powerful tool to prevent the development of the metabolic syndrome, since healthy diets have been shown to have a protective role against the components of the metabolic syndrome. Particularly, dietary fatty acids are capable of modulating

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the deleterious effects of these conditions, among other mechanisms, by modifications of the lipid composition of the membranes in insulin-sensitive tissues. However, there is still scarce data

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based of high-level evidence on the effects of dietary oils on the effects of the metabolic syndrome and its components.

This review summarizes the current knowledge on the effects of dietary oils on improving

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alterations of the components of the metabolic syndrome. It also examines their influence in the modulation of plasma membrane lipid composition and in the functionality of membrane proteins involved in insulin activity, like the insulin receptor, GLUT-4, CD36/FAT and ABCA-1, and their

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metabolic syndrome.

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effect in the metabolism of glucose, fatty acids and cholesterol, and, in turn, the key features of the

Keywords: metabolic syndrome, membrane, insulin resistance, phospholipids, fatty acids, dietary oil

ACCEPTED MANUSCRIPT 2. The Metabolic Syndrome

The metabolic syndrome is becoming a matter of great concern throughout the world. The overall prevalence of the metabolic syndrome in the USA is 33-39% (depending on the definition, see

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below), with significantly higher prevalence in women compared with men [1,2]. Europe is diverse

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in this regard, with countries such as Denmark with prevalences below 18% [2] or Spain with values above 30% [3]. However, this problem does not only affect wealthy countries. The prevalence of obesity is one of the greatest public health problems also in developing countries

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that have undergone important changes in lifestyle, eating habits and physical activity in the last years, with increasing dietary consumption of energy, animal proteins and fatty, affordable food [4]. In India, about 18% of the population have the metabolic syndrome and 10% of males and 18% of

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females in China [2].

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However, it is not all bad news. At least in the USA, the prevalence has remained stable overall since 2007 and has slightly declined in women according to Aguilar et al. [1]. Beltran-Sanchez et al. [5], also observed that the prevalence of metabolic syndrome has declined in the total

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population of USA when measuring clinical targets, but there is a divergence in trends for its individual components. For example, the prevalence of abdominal obesity increased from 45.4% in 1999/2000 to 56.1% in 2009/2010, while blood pressure and hypertriglyceridemia declined over the

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study period by 26-27%. The trend observed in the latest years might be associated with greater awareness of the metabolic syndrome and its health consequences, which may have contributed

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to improvements in optimizing treatment of some of the risk factors. Indeed, concurrent with improvements in dyslipidemia, Beltran-Sanchez et al. [5] observed higher utilization of drugs over time that target suboptimal lipid profiles such as statins, fibrates, and niacin derivatives. The metabolic syndrome is defined as a cluster of cardiovascular and type-2 diabetes mellitus (T2DM) risk factors related to insulin resistance, including hypertension, altered glucose metabolism, dyslipidemia, and abdominal obesity [6]. Although no universal definition has been accepted [7], some common features include the assessment of obesity (usually through body mass index (BMI) or waist circumference), the measurement of triglycerides (TG) and high-density lipoprotein (HDL)-cholesterol, and evaluation of risk factors associated with diabetes, like fasting glucose, glucose tolerance and insulin resistance [7]. The risk of suffering T2DM is five times as high in persons with metabolic syndrome and the risk of stroke or myocardial infarction is three times as high compared with those non-metabolic syndrome subjects [8]. Although the scientific and medical communities have not reached to a consensus regarding the diagnosis of metabolic syndrome (see Table 1 for the criteria established by different organizations), the most extensively accepted definition is that of the International Diabetes

ACCEPTED MANUSCRIPT Federation (IDF), which describes the metabolic syndrome as the presence of central obesity (waist circumference ≥ 94 cm in males and ≥ 80 cm in females), together with two or more of the following features: triglycerides ≥150 mg/dL, HDL-cholesterol <40 mg/dL in males and <50 mg/dL in females, systolic blood pressure ≥130 or diastolic blood pressure ≥85 mmHg and fasting plasma

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glucose ≥100 mg/dL or known T2DM. The IDF criteria are also used for children and adolescents,

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but with adaptations for the assessment of obesity [9].

Treatment of metabolic syndrome is focused to reduce the deleterious effects of its associated

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features, which implies a reduction in body weight, improvement of insulin sensitivity and reduction of blood pressure values and TG levels. The goal is to normalize these parameters, which can be achieved by pharmacological therapy. Diet may be a powerful contributor to the development of

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metabolic syndrome but in many cases, it is also the solution of choice or at least an adjuvant to drugs in the most severe cases. While the intake of dietary oils may actively participate in the

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development of insulin resistance and in the health consequences associated to it, they can also have a beneficial role. In fact, in most cases, dietary lipids are crucial before the pharmacological

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approach becomes necessary.

ACCEPTED MANUSCRIPT 3. Dietary lipids and the components of the metabolic syndrome

After decades of epidemiological, clinical and experimental research, it has become clear that consumption of specific dietary patterns has a profound influence on health outcomes, including

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the metabolic syndrome. Epidemiological studies suggest that Western-style dietary patterns

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promote the metabolic syndrome, while healthy diets rich in fruits, vegetables, grains, fish and lowfat dairy products have a protective role [10]. The quality of dietary fat is also determinant in the effect of diet on insulin sensitivity and the metabolic syndrome. Diets high in saturated fatty acids

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(SFA) impair both insulin sensitivity and blood lipids, while substituting carbohydrates or monounsaturated fatty acids (MUFA) for SFA revert these abnormalities in both healthy [11,12] and

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diabetic subjects [13,14].

Ros [15] concluded that natural foods and olive oil, as the main source of MUFA, provided a similar

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degree of glycemic control than low-fat diets. High-fat MUFA-enriched diets result in lower insulin requirements and lower plasma glucose concentrations compared to a low-fat, high-carbohydrate diet in patients with T2DM [16] and people who use olive oil present lower insulin resistance than

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those who use sunflower oil, a source of n-6 polyunsaturated fatty acids (PUFA) [17]. In addition, high-MUFA diets generally have more favorable effects on proatherogenic alterations associated with the diabetic status and the components of the metabolic syndrome. Of particular interest was

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the ability of an olive oil-rich Mediterranean diet to improve mild systemic inflammation in subjects

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with the metabolic syndrome [18,19].

In the PREDIMED intervention trial, logistic regression analysis confirmed that the Mediterranean diet supplemented with virgin olive oil was associated with metabolic syndrome reversion among individuals who were diagnosed with the syndrome at baseline [20]. After one year of intervention, the prevalence of the metabolic syndrome was reduced by 6.7% in the individuals receiving the Mediterranean diet supplemented with virgin olive oil [21]. Therefore, there is sufficient evidence to suggest that some dietary oils can have a beneficial effect not only against proatherogenic factors, but also against the prevalence of the metabolic syndrome. Dietary oils are not merely a fatty acid source, as they contain other minor components with important biological properties [22]. Some of these minor components of dietary oils have been shown to be associated with the components of the metabolic syndrome. 3.1. Dietary oils and obesity

Obesity increases the risk of diabetes, hypertension, coronary disease and non-alcoholic hepatic steatosis, either independently or within the context of the metabolic syndrome [23,24], being

ACCEPTED MANUSCRIPT central adiposity one of the key factors in the pathophysiology of insulin resistance and all the other components of the metabolic syndrome. Traditionally, nutritional advice for treating obesity has emphasized reducing energy intake by

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diminishing all kinds of dietary fat, which were replaced with carbohydrates. However, recent

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studies are pointing out that restricted energy diets that were relatively high in MUFA be more effective than the traditional low-fat diet for weight loss in obese persons [25]. Olive oil consumption was associated with non-significant lower likelihood of weight gain in the PREDIMED

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study [26], which is in striking contrast to the consistent association between unhealthy dietary patterns and a higher risk of weight gain and obesity [26,27]. The observed effect was attributed to a satiating effect of olive oil intake. In this regard, recent experimental evidence suggests that

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mobilization of intestinally-derived oleoylethanolamide, a lipid messenger of satiety, is enabled by

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the uptake of dietary oleic acid [28].

A meta-analysis of randomized controlled trials carried out by Bender et al. [29] showed that fish or fish oil consumption was associated with a weight reduction of 0.59 kg and BMI reduction of

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0.24 kg/m2, although the mechanisms could not be elucidated. Consequently, unsaturated fats appear to be more metabolically beneficial in regard to weight gain and its metabolic consequences compared to SFA, specifically MUFA ≥ PUFA > SFA [30]. Among PUFA-rich oils,

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obese humans who were supplemented with borage oil (890 mg of g-linolenic acid (18:3 n-6) per

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day) experienced a weight loss after 33 months of treatment [31]. 3.2. Dietary oils and plasma triglycerides

The knowledge of the metabolic pathways of TG and the consequences of hypertriglyceridemia are crucial in understanding the characteristic lipid alterations in insulin resistance and the metabolic syndrome [32]. Hypertriglyceridemia resulting from either increased TG production or decreased catabolism of TG-rich lipoproteins (TRL) directly influences low-density lipoprotein (LDL) and HDL composition and metabolism, which gives TG a central role in the pathogenesis of atherosclerosis. The size and fatty acid composition of the TRL particles are determinant in the preference of lipoprotein lipase (LPL) for VLDL or chylomicrons and in the hydrolysis rate of the TG and are highly dependent on the fatty acid composition of dietary oils [33]. Chylomicrons enriched in n-6 PUFA are processed by LPL at a faster rate than chylomicrons enriched in SFA, MUFA or n-3 PUFA, which may contribute to their increased rate of removal from circulation in the postprandial state [34]. However, Sato et al. [35] showed differences in LPL specificity for TRL enriched in palmitic, oleic, linoleic or a-linolenic acids (18:3, n-3), obtained from rats fed palm, olive, safflower and linseed oils, respectively. They found that the LPL specificity for TRL enriched in oleic acid was

ACCEPTED MANUSCRIPT higher than that for linoleic acid, and was associated to a reduction in lipoprotein fluidity, suggesting that this effect might enhance the affinity of the particles for the enzyme. The TG composition of dietary oils is a strong determinant also of the VLDL lipid composition and

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may play a role in regulating the metabolism of these TRL [33]. In the PREDIMED study, serum

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and VLDL TG concentrations were significantly lowered after 3-months of consuming a Mediterranean diet rich in virgin olive oil [36]. The intake of olive oil meals leads to the formation of higher-size TRL particles, with a higher triglyceride concentration per particle, compared with fat

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sources rich in SFA and n-6 PUFA [37,38]. In vitro studies carried out using artificial chylomicronlike particles (CRLP) indicate that when these particles are derived from palm or corn oil an increase in TG secretion in the form of VLDL from the liver occurs, but not when CRLP are derived

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from olive oil. In contrast, olive and corn oil-CRLP, compared to palm-derived CRLP, decreased the

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levels of messenger RNA for apolipoprotein (apo) B, a structural protein in VLDL [39]. Despite the beneficial effects that MUFA-rich diets may have on TG plasma levels, in severe hypertriglyceridemia, guidelines advocate the immediate use of TG-lowering drugs [40,41], which

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include fibrates, niacin, and n-3 PUFA. The TG-lowering ability of these fatty acids is well established and it is mediated by reducing TG synthesis, the incorporation of TG into VLDL and TG secretion, as well as enhancing TG clearance from VLDL particles [42]. However, the exact

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mechanisms of action are not completely understood. It has been proposed that they involve a decrease of hepatic lipogenesis by suppressing the expression of sterol regulatory element-binding

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protein-1c, which in turn, leads to decreased expression of fatty acid and TG synthesizing enzymes [43,44]. In addition, n-3 PUFA are thought to increase the β-oxidation of fatty acids, resulting in a reduction in available substrate required for TG and VLDL synthesis [42], to inhibit key enzymes involved in hepatic TG synthesis, such as phosphatidic acid phosphatase and diacylglycerol acyltransferase [45] and, finally, to increase the expression of LPL, the key enzyme responsible for VLDL and chylomicron catabolism [46]. In this regard, n-3 PUFA also exert effects on apo CIII activity. This apolipoprotein is a key contributor to hypertriglyceridemia, primarily due to its inhibitory actions on LPL. Docosahexaenoic acid (22:6 n-3, DHA), but not eicosapentaenoic acid (20:5 n-3, EPA), is believed to reduce apo CIII synthesis by regulating a number of hepatic transcription factors, such as hepatic nuclear factor-4-alpha and forkhead box-O transcription factor O1. Therefore, DHA enhances the hydrolysis of VLDL, resulting in greater lowering of plasma TG [47]. Ooi et al. [48] reported that a high-fish diet decreased nonfasting plasma TG, with concomitant reductions in TRL apo B-100 production and concentration and that dietary fish-derived n-3 fatty acids decreased TRL apoB-100 direct catabolism, thereby reducing VLDL-TG concentrations.

ACCEPTED MANUSCRIPT They also observed for the first time that dietary fish-derived n-3 fatty acids decreased TRL apo B48 concentration by decreasing TRL-apo B-48 secretion in humans. A systematic review of nine controlled trials in which stearic acid (18:0) replaced oleic or linoleic

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acids, serum TG increased 10–37% in 4 studies but did not change in 5 others [49]. Subsequently,

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it was proposed that the physical characteristics of the TG structure of SFA may impact on lipoprotein metabolism and consequently, lipemia. In a randomized crossover study, Sanders et al. [50] found that as the proportion of palmitic acid at the sn-2 position increased, postprandial

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lipemia decreased.

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3.3. Dietary oils and blood pressure

Despite our considerable knowledge on diet and blood pressure, some unanswered questions

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remain regarding dietary lipids. It is very well-known that reducing dietary SFA lower serum cholesterol, but their effects on blood pressure are less consistent. A systematic review of 15 randomized controlled trials published in 2015 showed no significant effect of SFA consumption on

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systolic blood pressure [51].

The effect of n-3 PUFA is much clearer. Randomized controlled trials providing fish oils have

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demonstrated that n-3 fatty acids lower blood pressure despite few contradictory results that are probably due to study design, relatively small sample sizes and/or an insufficient administration of

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n-3 fatty acids [52]. According to the most recent meta-analyses, consumption of n-3 PUFA can reduce blood pressure by −2.1/−1.6 mmHg, with the greatest effects in hypertensive individuals [52]. However, there is also evidence that EPA and DHA have differential effects on blood pressure [53]. The effect of DHA is stronger that that of EPA and it is accompanied by significant improvements in endothelial and smooth muscle function as well as reduced vasoconstrictor responses [54]. Possible mechanisms of the effect of n-3 PUFA on blood pressure include suppression of vasoconstrictor prostanoids, enhanced production and/or release of nitric oxide, reduced plasma noradrenaline, changes in calcium flux, antioxidative actions of n-3 fatty acids or an increase in HDL cholesterol, but also increased membrane fluidity [55]. Meta-analyses analyzing the effect of α-linolenic acid revealed that its consumption can also reduce diastolic blood pressure slightly, but the effect is lower that that of EPA or DHA [56]. Cross-sectional studies have also related olive consumption and blood pressure. In the Greek cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC) study, consumption of olive oil was associated with lower levels of both systolic and diastolic blood pressure [57] and in the Seguimiento University of Navarra (SUN) study a higher consumption of olive oil was associated with a lower risk of hypertension among men but not among women [58].

ACCEPTED MANUSCRIPT The lack of association in women was explained due to the lower number of hypertension cases included in the study. Intervention studies have also reported blood pressure reductions in hypertensive subjects after

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consumption of virgin olive oil [59,60]. More recently, supplementation with olive oil rich in phenolic

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compounds was effective in reducing blood pressure levels in a group of individuals from nonMediterranean countries [61]. In the PREDIMED trial, after a 3-month follow-up, systolic and diastolic blood pressures were significantly reduced in the group allocated to the Mediterranean-

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type diet supplemented with virgin olive oil [19].

These normotensive effects of virgin olive oil have been attributed to its minor components [62].

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These substances could help to revert the imbalance between increased oxidative stress and impaired antioxidant defense that affects endothelial function [63]] and modulate eicosanoid

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metabolism in endothelial cells [64][65]. In fact, a recent meta-analysis confirmed a moderate effect of virgin olive oil phenolic compounds on systolic blood pressure [66].

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3.4. Dietary oils and HDL-cholesterol

HDL has an important role in inflammation and oxidative stress, which may be impaired in subjects

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with diabetes or insulin resistance [67]. Perségol et al. [68] found that HDL taken from subjects with abdominal obesity and from those with type 1 and type 2 diabetes were defective in reversing the

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adverse effects of oxidized LDL compared with HDL from normal subjects. It is well known that consumption of high-MUFA diets can lower plasma LDL-cholesterol concentrations compared to PUFA without lowering HDL cholesterol concomitantly [69]. Stimulation of macrophage cholesterol efflux in the form of HDL is one of the mechanisms proposed for the effect of MUFA-rich oils on HDL-cholesterol. In mice, [70] showed a greater cholesterol efflux from peritoneal macrophages after olive oil consumption. The anti-atherogenic effect can be accompanied by reduced macrophage uptake of oxidized LDL via scavenger receptors, which has also been observed in mice consuming virgin olive oil [71]. In humans, a moderately hypoenergetic Mediterranean diet combined with an exercise program for 4 months ameliorated body weight and the cardiovascular parameters of the metabolic syndrome in a group of obese women, including HDL-cholesterol concentrations [72]. However, not all intervention studies have found increases in HDL-cholesterol concentrations. Mezzano et al. [73] compared the effect of a Mediterranean-type diet and a high-fat diet in two groups of 21 healthy young males over 90 days, failing to find changes in total plasma cholesterol, HDL and LDL in either study group at any time point.

The effect of olive oil on plasma HDL-cholesterol concentrations has been observed for other MUFA-rich dietary oils, regardless of their minor component composition. Long-term consumption

ACCEPTED MANUSCRIPT of virgin olive oil and high-oleic sunflower oil, both with a high content in oleic acid, modified in a similar way the plasma lipid profile of healthy women, as well as that of normo or hypercholesterolaemic hypertensive women [59]. Interestingly, both oils are capable of significantly increasing the plasma concentration of the cholesterol associated to HDL. Nevertheless, virgin

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olive oil phenolic compounds may also increase HDL-cholesterol concentrations. In this classic

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study on virgin olive oil phenolics, Covas et al. [22] showed that olive oil with a high phenolic content (366 mg/Kg) increased HDL-cholesterol in addition to reducing TG concentrations as

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compared with olive oil poor or devoid of these compounds.

Fish oil and n-3 PUFA have been shown to reduce TG as explained above, but their main fatty acids, EPA and DHA are believed to have differing effects on HDL-cholesterol [74]. A meta-analysis

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published in 2011, comparing the effects of DHA and EPA, showed that DHA was associated with a greater reduction in TG and a greater increase in LDL-cholesterol than EPA. In addition, DHA also

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raised HDL-cholesterol compared with placebo, whereas EPA did not [75]. Again, further research is still needed to elucidate the mechanisms and significance of these differences.

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Likewise, different dietary SFA can exert different effects on cholesterolemia [76]. According to a systematic review by Hunter et al. [49], diets high in stearic acid appear to have favorable effects on plasma LDL-cholesterol concentrations and the total cholesterol (TC)/HDL-cholesterol ratio

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compared with cholesterol-raising saturated fatty acids, such as palmitic acid and trans fatty acids. In contrast, stearic acid tends to increase both LDL-cholesterol and the TC/HDL-cholesterol ratio

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when compared with MUFA and PUFA. Regarding HDL-cholesterol, dietary stearic acid resulted to have neutral or lowering effects, when compared with unsaturated fatty acids. 3.5. Dietary oils and glucose

Animal and human studies have demonstrated that MUFA-rich diets can improve insulin sensitivity in both healthy [11,12] and diabetic [13] individuals. Administration of MUFA can increase plasma glucagon-like peptide-1 concentrations, which might contribute to increase insulin secretion [77]. In addition, b-cell function can be improved as the proportion of MUFA with respect to SFA in fatty meals is increased [78]. Experimental animal and cell culture studies have shown that SFA are less readily oxidized and accumulate as lipotoxic products, contributing to impairing b-cell function, while MUFA and PUFA appear to prevent these events by directing fat into oxidation or TG synthesis [79]. Perez-Jimenez et al. [80], who investigated the effects of a Mediterranean-style diet, a SFA-rich diet and a low-fat high-carbohydrate diet, found that plasma glucose was significantly decreased after the Mediterranean and high-carbohydrate diets, indicating an improvement in insulin sensitivity.

ACCEPTED MANUSCRIPT These results show that diets rich in MUFA tend to improve insulin sensitivity, but not all studies detected the same effect. The LIPGENE study showed no effect on insulin sensitivity after the administration of high-SFA, high-MUFA and high-carbohydrate diets with or without n-3 PUFA supplementation in patients with metabolic syndrome [81]. In the KANWU study, insulin sensitivity

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did not improve in healthy subjects when the MUFA content of the diet exceeded 37% of energy

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[12], indicating a potential interaction between fat quality and quantity. This is remarkable as another intervention study in patients with type 2 diabetes mellitus showed that a MUFA-enriched diet, with a 33% of total energy in the form of fat, resulted in lower insulin requirements and lower

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plasma glucose concentration compared to a low-fat (25% total energy) diet [16]. These discrepancies may be due to differences and/or insufficient cohort size, diverse clinical characteristics of the cohorts, the nature of the dietary fat modification, study duration, measures of

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insulin sensitivity and inappropriate study design.

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The effect of dietary oil minor components on glucose homeostasis and insulin sensitivity has not been extensively addressed. When rats were supplemented with oral b-sitosterol, they showed increased fasting insulin levels, decreased fasting glucose levels, improved oral glucose tolerance

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and increased insulin release from isolated rat pancreatic islet cells [82]. In vitro, b-sitosterol induced glucose uptake and stimulated both adipogenesis and lipolysis in adipocytes, which was related to down-regulation of the expression of proteins related to glucose transport and insulin

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signaling pathways [83]. Dietary supplementation with a-tocopherol decreased insulin and glucose levels in diet-induced obesity Sprague-Dawley rats [84]. In humans, lower serum a-tocopherol

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concentrations were independently associated with impaired insulin sensitivity. Maslinic and oleanolic have shown hypoglycemic effects by reducing insulin resistance in animal models of T2DM [85]. In addition, oleanolic acid may promote insulin signal transduction and inhibit oxidative stress-induced hepatic insulin resistance and gluconeogenesis [86]. There is also some evidence indicating that virgin olive oil phenolics might have also some hypoglycemic effect. Hydroxytyrosol was efficient to prevent hyperglycemia in alloxan-induced diabetic rats. In these animals, glucose concentration in plasma was decreased by 55% compared to untreated diabetic rats. The reduction was concomitant to an enhancement in the oxidant status and the activity of enzymatic defenses [87].

ACCEPTED MANUSCRIPT 4. Alterations of cell membrane composition in insulin resistance

Insulin resistance is the key feature pathogenically relating metabolic syndrome, T2DM and cardiovascular impairment. Thus, it is widely considered the major factor in the pathogenesis of

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metabolic syndrome. Insulin resistance is characterized by a reduction in the capacity of insulin to

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develop its normal physiological functions in tissues, causing an increase in baseline insulinemia as a compensatory response to maintaining glucose homeostasis [88]. This condition eventually results in pacreatic failure as b-cells are no longer capable of maintaining the hypersecretion of

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insulin, which leads to cell deterioration and a reduction of insulin secretion. Therefore, hyperinsulinemia caused by insulin resistance contributes to the failure of b-cells and eventually

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the development of diabetes.

The most relevant abnormalities of insulin resistance are observed in insulin targeted tissues, such

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as adipose tissue, liver and muscle [89]. In adipose tissue, in addition to diminishing glucose uptake, there are also alterations in lipid metabolism, such as impaired fatty acid uptake due to reduced LPL and fatty acid-binding protein 4 (FABP4) expression [90]. In addition, it is believed

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that insulin resistance causes increased non-esterified fatty acid (NEFA) release due to enhanced lipolysis [91], although this paradigm is being challenged lately. Karpe et al. [92] suggested that increased net lipolysis might not be occurring in the adipose tissue of obese subjects with insulin

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resistance, as in these individuals, the net NEFA release from adipocytes per kg of adipose tissue is actually decreased. In skeletic muscle, glucose intake is also reduced during insulin resistance,

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situation that is worsened by the increased fatty acid availability in plasma from adipose tissue, which can also be used for energetic purposes. In the liver, insulin resistance causes a decrease in glycogen synthesis together with an increase in gluconeogenesis, lipogenesis and protein synthesis.

Taken together, the presence of insulin resistance in these insulin sensitive target tissues results in major abnormalities such as hyperglycemia, hyperinsulinemia, and hypertriglyceridemia which are common features of the metabolic syndrome [89] Moreover, insulin resistance has also consequences in cell membrane lipid and protein composition, which alters its fluidity, structure and functionality.

ACCEPTED MANUSCRIPT 4.1. Membrane composition and structure

We have begun to appreciate in greater detail the importance of cell membrane lipids as essential regulators of insulin resistance, since changes in the dynamic properties of the cell membrane

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(e.g., membrane fluidity), could be one of the events by which obesity affects insulin sensitivity [93].

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According to the cell membrane hypothesis of insulin resistance, insulin action could be related to changes in cell membrane properties.

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Striking differences in the molecular configuration of fatty acids, particular in the degree of unsaturation, make for different properties when built into a cell membrane, as shown in Figure 1. High SFA content yields to rigid, unresponsive membranes, whereas increased unsaturation leads

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to improved membrane fluidity and responsiveness. For example, phosphatidylcholine containing a 18:0 acyl-chain in the sn-1 and sn-2 position has a melting point of approximately 55 ºC. Therefore,

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at mammalian body temperatures it exists in a solid aggregation state. However, if the 18:0 acylchain in the sn-2 position is replaced by 18:2 n-6, it maintains a liquid crystalline state until

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approximately 15 ºC [94].

Observations from both experimental animals and humans suggest a close association between insulin sensitivity and membrane lipid composition. In insulin-resistant rats, increased plasma

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membrane viscosity was associated with decreased insulin receptor activity in the liver [95]. In humans, a relation between the fatty acid composition of skeletal muscle membranes and insulin

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sensitivity has been demonstrated: the greater the percentage of PUFA, the enhanced insulin action [96]. Moreover, fasting plasma insulin levels were positively correlated with adipocyte membrane sphingomyelin and cholesterol content in obese women [97]. Multivariate regression analysis showed that membrane phosphatidyl-ethanolamine (PE) and sphyngomielin contents are independent predictors of insulin resistance in lean and overweight individuals [98].

Phospholipids are the major constituents of the biological membranes, and glycerophospholipids are the major class of naturally occurring phospholipids. However, phospholipids in biological membranes do not mix uniformly, but instead form microdomains or rafts of different lipid composition. Bulk membranes are enriched in glycerophospholipids (frequently containing unsaturated fatty acids) loosely packed in a liquid-disordered state displaying high fluidity. In contrast, membrane lipid rafts have a high content of glycerophospholipids, sphingolipids and glycosylphosphatidylinositol (bearing predominantly saturated fatty acids). These domains are also rich in cholesterol, which is thought to contribute to the tight packing of lipids by filling interstitial spaces between other lipid molecules [99]. A variant of these rafts termed caveolae appear as striated invaginations on the plasma membrane and are characterized by the presence of caveolin, a 21-kDa palmitoylated integral membrane protein [100]. In vitro studies have shown that caveolin

ACCEPTED MANUSCRIPT can function as a positive activator of insulin receptor, which binds to the scaffolding region of specific subtypes of caveolin [101]. Caveolin can also regulate hepatic lipid metabolism by modulating the fatty acid transit across the plasma membrane, thereby regulating TG storage and

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catabolism [102].

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The question of whether lipid rafts play a role in the pathogenesis of insulin resistance is receiving increasing attention. Most of the data derive from adipocytes, but evidence is also accumulating from other important insulin target tissues, including muscle, liver and pancreas [103]. The general

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notion that raft-dependent interactions may help to segregate signaling components is clearly acknowledged, demonstrated by the sensitivity of key insulin receptor-mediated signaling

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pathways to raft perturbation [104].

Despite not being targets of insulin action, the use of erythrocytes to investigate cell membrane

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composition is widely accepted. This model has several advantages, such as being an isolated plasma membrane with no intracellular organelles, no de novo synthesis of cholesterol and abundance of membrane available from a small blood sample [98]. In addition, changes in

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erythrocyte membrane phospholipid composition parallel those in membrane of other tissues, specially in obese subjects, providing a helpful model to study the effects of insulin resistance in

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plasma membrane [98].

Erythrocyte membrane fatty acid composition in obese adolescents differs from that in age and sex

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matched lean controls, reflecting a decrease in n-3 PUFA and MUFA and an increase in SFA, especially in very-long chain SFA, like 24:0 [105]. In contrast, inverse associations have been found between the homeostasis model assessment of insulin resistance (HOMA-IR) and EPA levels in the erythrocyte membrane of Inuits [106]. In addition, it is well known that erythrocyte membranes from obese subjects are characterized by a higher cholesterol/phospholipid ratio, which has been used as an index of membrane fluidity [107]. Membranes enriched in cholesterol and SFA and decreased in MUFA and PUFA showed enhancement of membrane rigidity (Figure 1), affecting the signaling pathways related to membrane proteins, such as the G-protein, membranebound protein kinase C (mPKC) activity, verapamil-sensi-tive Ca 2+ channels or extracellular signal-regulated kinase (ERK)-p38 mitogen-activated protein (MAP) kinase [108]. It has also been proposed that insulin resistance may not only be a cause but also a consequence of lipid disorders such as dyslipidemia and/or cell membrane phospholipid composition abnormalities. As a cause, hyperinsulinemia and/or insulin resistance could be responsible for changes in the membrane parameters, particularly membrane sphingomyelin and PE contents through alterations in the exchanges between cells and plasma lipoproteins, the stimulation of the cellular import of phospholipids or phospholipids biosynthesis [98]. The other hypothesis is that

ACCEPTED MANUSCRIPT insulin resistance is a consequence of membrane phospholipid abnormalities. Modifications of membrane phospholipid composition could have a role in the insulin action by altering membrane fluidity and, as a consequence, the insulin signaling pathway.

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4.2. Membrane fluidity and membrane protein associated to insulin resistance

Changes in the phospholipid fatty acid composition of membranes results in changes in the collective physicochemical properties of the bilayer, such as flexibility and fluidity (Figure 1). These

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modifications can, in turn, modulate the function of membrane proteins mediating insulin action. Biophysical and structural studies indicate that interactions of membrane proteins with lipid molecules are critical to their folding and stability [109], hampering glucose uptake, insulin binding,

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and downregulation of insulin receptor expression [98].

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Erythrocytes of patients with essential hypertension present decreased membrane fluidity, which is associated with hyperinsulinemia related to insulin resistance [110]. Membrane fluidity can also be altered in patients with metabolic syndrome by increased lipid peroxidation. Being rich in PUFA, in

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an environment rich in oxygen and oxygen-derived radicals, these fatty acids can be easily oxidized to lipid superoxides. According to Simon et al. [111], lipid peroxidation decreases lipid

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Insulin receptor

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fluidity and stiffens the membrane.

Insulin acts through the insulin receptor, a plasma membrane receptor tyrosine kinase. Upon insulin binding, the receptor is autophosphorylated on tyrosine residues and can thereby phosphorylate other proteins, transducing the signal to metabolic and mitogenic signaling networks (Figure 2) [112]. Down-regulation of insulin receptor activity and a reduction in tyrosine phosphorylation of both the insulin receptor and the insulin receptor substrate (IRS-1) occurs in all the major insulin-sensitive tissues and may be responsible for the development of insulin resistance [113]. The activity of the insulin receptor, as well as its affinity to insulin depend on the structure and functional integrity and fluidity of the cell membrane, which, in turn, are dependent on the lipid composition of the membrane. Decreased fluidity of the membrane by increased SFA content in phospholipids leads to a decrease in the number of insulin receptors and the affinity of insulin to them. On the contrary, the presence of PUFA (in particular n-3 fatty acids) in plasma membrane phospholipids increases its fluidity and has been associated with improved insulin sensitivity [114]. Fatty acids can also modulate the action of PKC [115], whose activation can lead to increased serine/threonine phosphorylation of the IRS. This conformational change leads to decreased

ACCEPTED MANUSCRIPT tyrosine phosphorylation of the IRS, thus impairing the whole downstream insulin signaling pathway and causing insulin resistance [116].

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Glucose transport (GLUT)

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Glucose transport across the membranes may be strongly influenced by membrane fluidity. Specific transporter proteins (glucose transporters, GLUT) are required to facilitate glucose diffusion into cells. GLUT are integral membrane proteins that contain 12 membrane-spanning

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helices with both the amino and carboxyl termini exposed on the cytoplasmic side of the membrane. Such proteins facilitate net movement of glucose only in the thermodynamically

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favored direction [117].

In the basal state, GLUT4 cycles continuously between the plasma membrane and one or more

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intracellular compartments [118]. GLUT4 differs from other glucose transporters in that about 90% is sequestered in intracellular vesicles in the absence of insulin. Once the insulin receptor has been stimulated, the intracellular stores are translocated to muscle plasma membranes. A cascade

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of events culminates finally in membrane fusion with GLUT4 containing vesicles. These plasma membrane localized transporters subsequently facilitate the influx of plasma glucose into the cell

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[117].

The fatty acid composition of membrane phospholipids may influence glucose transport by GLUT.

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Garvey et al. [119] observed that in patients with obesity, impaired glucose intolerance, type II diabetes and gestational diabetes impaired GLUT-4 function or translocation occurs. Weijers et al [117] suggested that a shift from unsaturated towards SFA in phospholipid membranes counteracts the machinery responsible for GLUT4 insertion into plasma membrane, by creating a more tight packing of phospholipids and affecting glucose transport and insulin sensitivity. In addition, cholesterol depletion from plasma membrane results in an increase in the basal-state plasma membrane level of GLUT4 [120]. Activation of phosphatidylinositol-3 kinase (PI3K) is one of the important steps in insulin signaling downstream of IRS, as it is involved in the translocation of GLUT4 to the cell membrane in response to the insulin signal but its activity in response to insulin can be totally inhibited by fatty acids [121]. However, whether fatty acids act on PI3K directly or mediated by PKC is still unclear. On the other hand, it has been suggested that PUFA can act as ligands of peroxisome proliferatoractivated receptor-gamma (PPAR-g) or modulate its expression, thus increasing GLUT4 transcription and synthesis, and improving insulin resistance [116,122].

ACCEPTED MANUSCRIPT Fatty acid transport (CD36/FAT and FABPpm)

Fatty acid uptake is believed to be mostly dependent on fatty acid transport proteins (FATPs), plasma membrane fatty acid binding protein (FABPpm) and fatty acid translocase (CD36/FAT).

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CD36/FAT is expressed mainly in insulin-sensitive tissues, such as adipose tissue, skeletal muscle

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and heart. In contrast, CD36/FAT expression in liver is low because endothelial cells in hepatic circulation provide a profusion of fatty acids and concentration gradient across the membrane is always favorable to the cells. CD36/FAT overexpression, which is regulated by liver X receptor

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(LXR), pregnane X receptor (PXR) and PPAR-γ, increases hepatic TG storage by increasing NEFA uptake [123].

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During insulin stimulation, CD36 translocates from endosomal pools to the plasma membrane to facilitate fatty acid uptake [124]. In the cytoplasm, fatty acids bind to cytosolic fatty acid-binding

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protein (FABPc) after which they are transported through the cytoplasm to the mitochondria (Figure 3). In the absence of caveolin, CD36/FAT is mis-targeted out of detergent-resistant membranes,

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resulting in reduced fatty acid uptake [125].

Although CD36/FAT does not play a major role in fatty acid uptake in normal liver, increased hepatic CD36/FAT expression has been observed in various pathologic conditions such as insulin

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resistance and type 2 diabetes mellitus [123]. In monocytes of diabetic patients, increased levels of CD36 are highly correlated with insulin resistance. [126] Current evidence indicates that the

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increase in CD36 is caused by defective insulin signaling, which may be mediated by PI3K [126]. In addition, a deficiency in CD36/FAT expression in individuals has been associated with metabolic syndrome. Asian and African individuals have a relatively frequent genetic CD36 deficiency, which is associated to some features of the metabolic syndrome [127]. Cholesterol transport (ABCA1)

Hyperinsulinemia, in the context of insulin resistance, lowers HDL-C in part via lowering the ATPbinding cassette transporter (ABCA1, ABCG1 and ABCG4) level or reducing its specific activity through phosphorylation at the Tyr1206 site [128]. In addition to the unmediated aqueous diffusion process, cellular cholesterol removal is thought to be mediated by scavenger receptor class B type I (SR-BI) and ABCA-1, the latter being considered the most important [129]. Lipid-free and lipidpoor apo AI-containing particles, designated preβ−HDL, are recognized as initial acceptors of cellderived cholesterol via the ABCA1-mediated system, whereas phospholipid-rich mature HDL may promote cellular cholesterol efflux via SR-BI, ABCG1 and ABCG4 [130]. ABCA1 is highly sensitive to variations in membrane physicochemical properties [131]. ABCA1 is widely expressed, but it is

ACCEPTED MANUSCRIPT the hepatic ABCA1, and to a lesser extent the intestinal ABCA1, that play the most important role in sustaining circulating HDL-C level [132].

In addition, it has been suggested that ABCA1 is important for pancreatic b-cell function. A study

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developed in ABCA1 knockout mice revealed that absence of ABCA1 in the b-cell led to

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accumulation of cellular cholesterol, which, in turn, resulted in an impairment of b-cell function based on impaired insulin exocytosis [133]. The translatability of this finding was confirmed in human subjects homozygous with ABCA1 mutations [134]. Finally, in addition to diminished

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assembly of large nascent HDL particles, silencing ABCA1 in McArdle rat hepatoma cells results in increased secretion of large, TG-enriched VLDL particles, highlighting a novel role for hepatic

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ABCA1 in the metabolism of TG [135].

ACCEPTED MANUSCRIPT 5. Effects of dietary fats on membrane functionality in relation to insulin resistance

Although, as we saw above, there is evidence indicating that dietary lipids can have positive effects on the features of the metabolic syndrome, the mechanisms and effects on the molecular and

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structural bases underlying the physiological process are still largely unknown. The type and

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amount of dietary lipids influence the lipid composition of cell membranes and modulate the interactions with proteins involved in the regulation of insulin sensitivity but also processes associated with other components of the metabolic syndrome like dyslipidemia and hypertension.

structural properties of plasma membranes[107].

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5.1. High-fat diets

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The effects, at least in part, are probably mediated by modification of the composition and

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High fat diets lead to increased fatty acid delivery to insulin sensitive cells, resulting in augmented reactive oxygen species (ROS) production (as a by-product of increased fatty acid oxidation) and accumulation of lipid intermediates such as diglycerides (DG) and ceramides. These latter

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compounds have a profound impact on insulin signaling. Kinases, notably c-Jun N-terminal kinase (JNK) and IkB kinase (IKK), are activated by ROS, and PKC is activated by DG. Together, they down-regulate insulin action through serine phosphorylation of IRS-1, which leads to its inhibition

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[127]. Furthermore, ceramides neutralize insulin action by inhibiting Akt [136]. Overall, increased lipid delivery to the cells results in accumulation of lipid metabolites, most notably ceramides and

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DG, and generation of ROS, which promote a permanent CD36 relocation and a decreased insulinstimulated GLUT4 translocation. High-fat diets are also known to impair glucose transport in muscle by reduced GLUT-4 translocation to the plasma membrane of muscle tissue [137]. Exposure to a high-fat diets induces cardiac contractile dysfunction, which is associated with a permanent relocation of CD36 to the plasma membrane [138]. The associated mechanism might be related to activation of AMPK, PI3KAkt and PPAR, which are all critical for CD36 translocation to the plasma membrane via different pathways [139]. 5.2. High-cholesterol diets

Manipulation of membrane cholesterol and phospholipids has an important impact on insulin signaling, as it modifies the lipid composition of microdomains that are the site of insulin action. Reduction of sphyngomielin in plasma membrane caveolae of liver, adipose tissue and muscle enhances insulin sensitivity in sphingomyelin synthase 2 gene knockout mice [140]. On the other hand, alteration of membrane cholesterol composition impairs downstream propagation of the

ACCEPTED MANUSCRIPT insulin signal, as indicated by decreased phosphorylation of the insulin receptor and Akt [141] and translocation of GLUT4 to the membrane [120]. Nevertheless, others have suggested that cholesterol seems to have no effect on insulin sensitivity, as animals fed on a high-cholesterol diet for 3 weeks showed similar glucose disappearance constants compared with control animals. In

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these animals, an increase in insulin level was observed, which was accompanied by a decrease

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in NEFA and significant reduction in circulating TG. This was associated with an inadequate synthesis of cholesterol-rich and TG-poor lipoproteins [102]. The effects were related to alterations in the composition of liver caveolae microdomains by increased cholesterol content in the

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membranes.

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5.3. Fatty acid unsaturation degree

Cell membrane phospholipid composition is regulated by the fatty acid composition of dietary fat

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[142], being especially sensitive to n-6 and n-3 PUFA, with a preference for the latter [116]. In contrast, membrane SFA and MUFA content is not as dependent on the dietary fatty acid profile, as these fatty acids can be synthesized endogenously. Animal and human studies have accumulated

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an impressive body of evidence to establish the connection between dietary lipids, membrane lipid profiles and insulin resistance, with high SFA diets leading to insulin resistance, whereas diets high in n-3, with a low n-6/ n-3 ratio, keeping insulin action at normal levels [116]. Many reports have

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shown that a high intake of dietary SFA significantly worsens insulin resistance, in particular through modifications in the composition of cell membrane phospholipids [143], including changes

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in D5 and D9 desaturase activities and CD36 expression [144]. In humans, a reduced activity of D5 desaturase is associated with insulin resistance [12].

The effect has also been extended to MUFA, since both palmitic and oleic acids have been shown to have the capability to induce insulin resistance in the liver, which was related to the intracellular accumulation of different lipid fractions [145]. For instance, palmitic acid exposure resulted in the accumulation of ceramides and DG, developing inhibition of insulin-stimulated Akt activation with the reduction of hepatic GLUT-2 expression and decreased glucose uptake. On the other hand, exposure to oleic acid induced accumulation of DG and TG, but not ceramides, also resulting in insulin resistance in hepatocytes. In both cases, lipid accumulation in the cells was enhanced by increased FABPpm and FAT/CD36 expression and translocation of the transporters to plasma membrane.

However, these findings disagree with what was reported by Ryan et al. [146], who examined the relationship between changes in membrane fatty acid composition and glucose transport and found a reduction in insulin resistance when a linoleic acid-rich diet was changed to oleic acid-rich diet. This was attributed to a reduction in its fluidity when the membrane was enriched in oleic acid.

ACCEPTED MANUSCRIPT Indeed, it has been shown that consumption of olive oil-rich diets increases the concentration of oleic acid in plasma membrane lipids of different rat and human cells, improving membrane functionality [59,142].

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Virgin olive oil consumption induces significant changes of specific fatty acid concentrations in

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plasma membrane phospholipids of hypertensive subjects, mainly due to a rise in the proportion of oleic acid. These changes have been shown to improve the localization and activity of several membrane-associated proteins and processes related to regulation of blood pressure [147,148]. G-

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protein expression, involved in cell signal transduction and the regulation of blood pressure, is also modulated by changes in membrane lipids [149]. Therefore, the effects of virgin olive oil on blood pressure in hypertensive patients, could be originated by modulation of the interaction of G-

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proteins and other signal-related proteins, in addition or alternatively to membrane fluidity [142]. In the PREDIMED Study, administration of a Mediterranean-style diet reduced cholesterol content

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and increased that of phospholipids in ertyhtrocyte membranes [107]. Although only minor changes were found in the phospholipid fatty acid profile of patients, phospholipids classes composition was modified to different extents. For instance, PE was reduced after following the a low-fat diet but

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increased after a Mediterranean diet supplemented with virgin olive oil. In addition, sphingomyelin and lysophosphatidyl-choline concentrations were reduced in erythrocytes membranes of the group receiving virgin olive oil, which corroborates what had been previously found in SHR rats

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[150]. It was also observed that reconstituted membranes from the Mediterranean diet-virgin olive oil group showed a higher propensity to form nonlamellar HII structures that correlated with an

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increase in PE. It has been shown in model membranes, that HII -phase propensity correlates with an increase in G-protein localization or PKC activity [151], demonstrating the influence of the membrane structure on cell signaling proteins that participate in insulin sensitivity. Part of the effect of virgin olive oil has also been attributed to polyphenols as it has been reported that they have lipid-lowering properties, down-regulate CD36 gene expression and modulate desaturase activity in insulin sensitive tissues. In rat muscle, grape polyphenols prevent TG accumulation caused by a high-saturated high-fat diet and modify membrane phospholipid fatty acid composition by increasing n-3 PUFA content [144]. Diets rich in n-3 PUFA have been shown to prevent obesity, hyperlipidemia, but also, adipocyte insulin resistance in rats [52]. Although the exact mechanism by which n-3 PUFA decrease insulin resistance is presently not known, incorporation of n-3 PUFA into cell membrane phospholipids is favored and increases cell membrane fluidity and as result, the expression, affinity, and number of the insulin receptor [113]. In addition, it has been proposed that n-3 PUFA increase in GLUT-4 mRNA and protein level in adipocytes [152]. Moreover, insulin enhances the activity of D6 and D5 desaturases [153], which are key in the process of EPA and DHA biosynthesis.

ACCEPTED MANUSCRIPT Human and animal studies have repeatedly shown that an increase in membrane unsaturation, and especially in n-3 PUFA, is associated with an higher insulin sensitivity [12]. In rats, Guelzim et al. [154] reported that diets differing in their fatty acid profile resulted in markedly different fatty acid

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profile in red blood cells, muscle and liver, without possible confounding factors due to food intake.

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Diets rich in a-linolenic acid or fish oil increase the presence in n-3 PUFA in these tissues at the expense of n-6 PUFA [154,155]. These findings may explain why insulin sensitivity was improved in these animals compared to those receiving oleic acid, as assessed by lower HOMA-IR and

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enhanced activation of the early steps of insulin signalling in the liver. This overall improvement in insulin sensitivity was associated with the enrichment of cell membranes in n-3 PUFA. Among after n-3 PUFA administration to the animals.

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tissues, liver appeared to be the most responsive to the diet showing higher unsaturation indexes

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Fickova et al. [156] showed that PUFA modulate insulin sensitive glucose uptake in rat adipocytes fed diets rich in n-6 PUFA (sunflower oil) or n-3 (fish oil) for one week, being more apparent for the former. In contrast, data from an older study by Nagy et al. [157] had previously shown that feeding

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rats diets rich in DHA and safflower oil (n-6 PUFA) had impaired their adipocyte glucose uptake. Incorporation of arachidonic acid (20:4 n-6, AA), a product of linoleic acid metabolism, decreased

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the ABCA1 functionality in cardiomyocytes, whereas the membrane incorporation of DHA increased it [158]. Moreover, PUFA modulate cellular eicosanoids formed from AA and EPA, and

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balance influences several signal transduction pathways in various cell types [159]. Molulation of ABCA1 in macrophages by fatty acids is controversial and depends on the model used. In J774 macrophages, AA and EPA decreased the ABCA1 functionality, whereas DHA had the opposite effect. ABCA1 expression did not account for these variations, which also seemed to not be related to the membrane fluidity state. However, in human primary macrophages, the impact of DHA supplementation was somewhat different, as a concomitant increase in DHA and EPA was observed, thus revealing an efficient retroconversion pathway. The results of the impact of EPA on the membrane phospholipid profile also contrasted with those of the J774 mouse cell model, as an increase in EPA and DPA of the same magnitude was found [160]. Conversely to mouse macrophages, AA and DHA had no impact on ABCA1-mediated cholesterol efflux from human macrophages. However, as for J774 mouse macrophages, EPA membrane incorporation induced a dose-dependent reduction in ABCA1 functionality and diminished cholesterol efflux [160]. The variations of ABCA1 functionality were not related to alterations of membrane fluidity, as all tested PUFA increased the unsaturation index. In contrast, it was proposed that the observed effects might be related to a PKA-dependent pathway involving eicosanoid formation [160].

ACCEPTED MANUSCRIPT Nevertheless, when treated with PUFA, cells tend to compensate for the fatty acid incorporation by generating more SFA, leading to partial rigidification of the membrane, as observed in HepG2 hepatocytes [161]. On the other hand, they generate more desaturated fatty acids when saturated

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lipids are added into the culture media.

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Trans fatty acids incorporation to plasma membranes has been shown to decrease ABCA1 function by reducing membrane fluidity [131]. ABCA1 transporter is highly sensitive to variations in the physicochemical properties of the cell membrane [162]. While higher membrane fluidity gives a

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more favorable environment for ABCA1 function, trans acyl chains in the membrane adopt

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extended configurations similar to saturated acyl chains [163], thus reducing fluidity.

ACCEPTED MANUSCRIPT 6. Conclusion

The metabolic syndrome is of great concern worldwide because it increases enormously the risk of suffering T2DM and cardiovascular disease. Fortunately, epidemiological studies have shown that

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healthy diets rich in fruits, vegetables, grains, fish and low-fat products have a protective role

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against the components of the metabolic syndrome, such as hypertension, hyperglycemia, hypertriglyceridemia, obesity and low HDL levels. In this regard, dietary lipids are at the same time capable of developing these risk factors and to ameliorate them. SFA are overall deleterious, while

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MUFA and PUFA, as well as some of the minor components present in some dietary oils, are beneficial for these factors, despite some the different controversies raised.

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Insulin resistance is the key feature in the pathogenesis metabolic syndrome. However, it has been suggested that insulin resistance might be at the same time cause and consequence of impaired

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membrane lipid composition in plasma membranes of insulin-sensitive tissues like liver, muscle and adipose tissue. This is of importance, because it is well-known that dietary treatment is

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capable of altering the lipid composition of plasma membrane. In any case, modification of the fatty acid and phospholipid composition of plasma membrane leads to changes in the functionality of proteins involved in insulin activity, like the insulin receptor,

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GLUT-4, CD36/FAT and ABCA-1, which have important roles in the metabolism of glucose, fatty acids and cholesterol, and, in turn, in the key features of the metabolic syndrome. In consequence,

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modification of plasma membrane lipid composition with dietary lipids not only might protect against the development of insulin resistance, but also it can improve some of the altered markers of the metabolic syndrome. In fact, by modifying cell membrane composition, dietary oils are capable of reducing serum glucose and triglyceride levels, increasing those of HDL-cholesterol and lowering blood pressure.

These effects are probably due to improvements in membrane fluidity and restoration of lipid composition in the membrane microdomains that are involved in the activity of the aforementioned proteins. In this regard, SFA, cholesterol and trans fatty acids are usually associated with increased rigidity, whereas MUFA and PUFA have been related with the opposite. However, there are still discrepancies regarding the differential effects of individual fatty acids. These discrepancies are often due to differences in the concentrations at which they are present in the diet, their chain length and unsaturation degree, but also to differences in the experimental design of the studies, such as the different animal models used or the different cells lines employed.

Large randomized clinical trials, like the Predimed study, have clearly shown that dietary oils, in the context of healthy diets, can be effective in improving all the features associated to the metabolic

ACCEPTED MANUSCRIPT syndrome and that the effect is associated may be, at least in part, associated to modifications in plasma membrane composition and structure. Therefore, there is need of well-designed, standardized and sufficiently large clinical trials to ascertain which and to which extent fatty acids can improve the development of the metabolic syndrome by modulating insulin resistance via

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modification of plasma membrane lipids.

ACCEPTED MANUSCRIPT References

[1] M. Aguilar, T. Bhuket, S. Torres, B. Liu, R.J. Wong, Prevalence of the metabolic syndrome in the United States, 2003-2012, JAMA, 313 (2015) 1973–1974.

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[2] S. O’Neill, L. O’Driscoll, Metabolic syndrome: a closer look at the growing epidemic and its

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associated pathologies, Obes. Rev. Off. J. Int. Assoc. Study Obes., 16 (2015) 1–12. [3] D. Fernández-Bergés, A. Cabrera de León, H. Sanz, R. Elosua, M.J. Guembe, M. Alzamora, T. Vega-Alonso, F.J. Félix-Redondo, H. Ortiz-Marrón, F. Rigo, C. Lama, D. Gavrila, A. Segura-

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Fragoso, L. Lozano, J. Marrugat, Metabolic syndrome in Spain: prevalence and coronary risk associated with harmonized definition and WHO proposal DARIOS study, Rev. Esp. Cardiol. Engl. Ed, 65 (2012) 241–248.

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[4] C. Papandreou, T.A. Mourad, C. Jildeh, Z. Abdeen, A. Philalithis, N. Tzanakis, Obesity in Mediterranean region (1997-2007): a systematic review, Obes. Rev. Off. J. Int. Assoc. Study

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Obes., 9 (2008) 389–399.

[5] H. Beltrán-Sánchez, M.O. Harhay, M.M. Harhay, S. McElligott, Prevalence and trends of metabolic syndrome in the adult US population, 1999-2010, J. Am. Coll. Cardiol., 62 (2013)

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697–703.

[6] R. Weiss, A.A. Bremer, R.H. Lustig, What is metabolic syndrome, and why are children getting it?, Ann. N. Y. Acad. Sci., 1281 (2013) 123–140. Rep., 16 (2014) 436.

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[7] S. Owens, R. Galloway, Childhood obesity and the metabolic syndrome, Curr. Atheroscler.

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[8] K.G.M.M. Alberti, P. Zimmet, J. Shaw, IDF Epidemiology Task Force Consensus Group, The metabolic syndrome--a new worldwide definition, Lancet Lond. Engl., 366 (2005) 1059–1062. [9] P. Zimmet, K.G.M. Alberti, F. Kaufman, N. Tajima, M. Silink, S. Arslanian, G. Wong, P. Bennett, J. Shaw, S. Caprio, IDF Consensus Group, The metabolic syndrome in children and adolescents - an IDF consensus report, Pediatr. Diabetes, 8 (2007) 299–306. [10] P.L. Lutsey, L.M. Steffen, J. Stevens, Dietary intake and the development of the metabolic syndrome: the Atherosclerosis Risk in Communities study, Circulation, 117 (2008) 754–761. [11] J. Salas, J. López Miranda, S. Jansen, J.L. Zambrana, P. Castro, J.A. Paniagua, A. Blanco, F. López Segura, J.A. Jiménez Perepérez, F. Pérez Jiménez, J.A. Perepérez, [The diet rich in monounsaturated fat modifies in a beneficial way carbohydrate metabolism and arterial pressure], Med. Clínica, 113 (1999) 765–769. [12] B. Vessby, M. Uusitupa, K. Hermansen, G. Riccardi, A.A. Rivellese, L.C. Tapsell, C. Nälsén, L. Berglund, A. Louheranta, B.M. Rasmussen, G.D. Calvert, A. Maffetone, E. Pedersen, I.B. Gustafsson, L.H. Storlien, KANWU Study, Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: The KANWU Study, Diabetologia, 44 (2001) 312–319.

ACCEPTED MANUSCRIPT [13] M. Parillo, A.A. Rivellese, A.V. Ciardullo, B. Capaldo, A. Giacco, S. Genovese, G. Riccardi, A high-monounsaturated-fat/low-carbohydrate diet improves peripheral insulin sensitivity in noninsulin-dependent diabetic patients, Metabolism., 41 (1992) 1373–1378. [14] U. Schwab, L. Lauritzen, T. Tholstrup, T. Haldorssoni, U. Riserus, M. Uusitupa, W. Becker,

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Effect of the amount and type of dietary fat on cardiometabolic risk factors and risk of

RI P

developing type 2 diabetes, cardiovascular diseases, and cancer: a systematic review, Food Nutr. Res., 58 (2014).

[15] E. Ros, Dietary cis-monounsaturated fatty acids and metabolic control in type 2 diabetes, Am.

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J. Clin. Nutr., 78 (2003) 617S–625S.

[16] A. Garg, High-monounsaturated-fat diets for patients with diabetes mellitus: a meta-analysis, Am. J. Clin. Nutr., 67 (1998) 577S–582S.

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[17] F. Soriguer, G. Rojo-Martínez, I. Esteva de Antonio, M.S. Ruiz de Adana, M. Catalá, M.J. Merelo, M. Beltrán, F.J. Tinahones, Prevalence of obesity in south-east Spain and its relation

MA

with social and health factors, Eur. J. Epidemiol., 19 (2004) 33–40. [18] K. Esposito, R. Marfella, M. Ciotola, C. Di Palo, F. Giugliano, G. Giugliano, M. D’Armiento, F. D’Andrea, D. Giugliano, Effect of a mediterranean-style diet on endothelial dysfunction and

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markers of vascular inflammation in the metabolic syndrome: a randomized trial, JAMA J. Am. Med. Assoc., 292 (2004) 1440–6.

[19] R. Estruch, M.A. Martínez-González, D. Corella, J. Salas-Salvadó, V. Ruiz-Gutiérrez, M.I.

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Covas, M. Fiol, E. Gómez-Gracia, M.C. López-Sabater, E. Vinyoles, F. Arós, M. Conde, C. Lahoz, J. Lapetra, G. Sáez, E. Ros, PREDIMED Study Investigators, Effects of a

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Mediterranean-style diet on cardiovascular risk factors: a randomized trial, Ann. Intern. Med., 145 (2006) 1–11.

[20] N. Babio, M. Bullo, J. Salas-Salvado, Mediterranean diet and metabolic syndrome: the evidence, Public Health Nutr., 12 (2009) 1607–1617. [21] J. Salas-Salvadó, A. Garcia-Arellano, R. Estruch, F. Marquez-Sandoval, D. Corella, M. Fiol, E. Gómez-Gracia, E. Viñoles, F. Arós, C. Herrera, C. Lahoz, J. Lapetra, J.S. Perona, D. MuñozAguado, M.A. Martínez-González, E. Ros, Components of the Mediterranean-type food pattern and serum inflammatory markers among patients at high risk for cardiovascular disease, Eur. J. Clin. Nutr., 62 (2008) 651–659. [22] M.I. Covas, V. Ruiz-Gutiérrez, R. Torre, A. Kafatos, R.M. Lamuela-Raventós, J. Osada, R.W. Owen, F. Visioli, Minor Components of Olive Oil: Evidence to Date of Health Benefits in Humans, Nutr. Rev., 64 (2006) S20–S30. [23] P.G. Kopelman, Obesity as a medical problem, Nature, 404 (2000) 635–643. [24] N. Friedman, E.L. Fanning, Overweight and obesity: an overview of prevalence, clinical impact, and economic impact, Dis. Manag. DM, 7 Suppl 1 (2004) S1-6.

ACCEPTED MANUSCRIPT [25] H. Schröder, J. Marrugat, J. Vila, M.I. Covas, R. Elosua, Adherence to the traditional mediterranean diet is inversely associated with body mass index and obesity in a spanish population, J. Nutr., 134 (2004) 3355–3361. [26] M. Bes-Rastrollo, A. Sánchez-Villegas, C. de la Fuente, J. de Irala, J.A. Martinez, M.A.

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Martínez-González, Olive oil consumption and weight change: the SUN prospective cohort

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study, Lipids, 41 (2006) 249–256.

[27] M.A. Pereira, A.I. Kartashov, C.B. Ebbeling, L. Van Horn, M.L. Slattery, D.R. Jacobs, D.S. Ludwig, Fast-food habits, weight gain, and insulin resistance (the CARDIA study): 15-year

SC

prospective analysis, Lancet Lond. Engl., 365 (2005) 36–42.

[28] G.J. Schwartz, J. Fu, G. Astarita, X. Li, S. Gaetani, P. Campolongo, V. Cuomo, D. Piomelli, The lipid messenger OEA links dietary fat intake to satiety, Cell Metab., 8 (2008) 281–288.

NU

[29] N. Bender, M. Portmann, Z. Heg, K. Hofmann, M. Zwahlen, M. Egger, Fish or n3-PUFA intake and body composition: a systematic review and meta-analysis, Obes. Rev. Off. J. Int. Assoc.

MA

Study Obes., 15 (2014) 657–665.

[30] S. Krishnan, J.A. Cooper, Effect of dietary fatty acid composition on substrate utilization and body weight maintenance in humans, Eur. J. Nutr., 53 (2014) 691–710.

ED

[31] M.A. Schirmer, S.D. Phinney, Gamma-linolenate reduces weight regain in formerly obese humans, J. Nutr., 137 (2007) 1430–1435. [32] M. Miller, N.J. Stone, C. Ballantyne, V. Bittner, M.H. Criqui, H.N. Ginsberg, A.C. Goldberg, W.J.

PT

Howard, M.S. Jacobson, P.M. Kris-Etherton, T. a Lennie, M. Levi, T. Mazzone, S. Pennathur, Triglycerides and cardiovascular disease: a scientific statement from the American Heart

AC CE

Association, Circulation, 123 (2011) 2292–333. [33] J.S. Perona, J. Cañizares, E. Montero, J.M. Sánchez-Domínguez, Y.M. Pacheco, V. RuizGutierrez, Dietary virgin olive oil triacylglycerols as an independent determinant of very lowdensity lipoprotein composition, Nutr. Burbank Los Angel. Cty. Calif, 20 (2004) 509–514. [34] K.M. Botham, M. Avella, A. Cantafora, E. Bravo, The lipolysis of chylomicrons derived from different dietary fats by lipoprotein lipase in vitro, Biochim. Biophys. Acta, 1349 (1997) 257– 263. [35] K. Sato, T. Takahashi, Y. Takahashi, H. Shiono, N. Katoh, Y. Akiba, Preparation of chylomicrons and VLDL with monoacid-rich triacylglycerol and characterization of kinetic parameters in lipoprotein lipase-mediated hydrolysis in chickens, J. Nutr., 129 (1999) 126–131. [36] J.S. Perona, M.I. Covas, M. Fitó, R. Cabello-Moruno, F. Aros, D. Corella, E. Ros, M. Garcia, R. Estruch, M.A. Martinez-Gonzalez, V. Ruiz-Gutierrez, Reduction in systemic and VLDL triacylglycerol concentration after a 3-month Mediterranean-style diet in high-cardiovascularrisk subjects, J. Nutr. Biochem., 21 (2010) 892–898. [37] K.G. Jackson, M.D. Robertson, B. A. Fielding, K.N. Frayn, C.M. Williams, Olive oil increases the number of triacylglycerol-rich chylomicron particles compared with other oils: an effect retained when a second standard meal is fed, Am. J. Clin. Nutr., 76 (2002) 942–9.

ACCEPTED MANUSCRIPT [38] P. Perez-Martinez, J.M. Ordovas, A. Garcia-Rios, J. Delgado-Lista, N. Delgado-Casado, C. Cruz-Teno, a Camargo, E.M. Yubero-Serrano, F. Rodriguez, F. Perez-Jimenez, J. LopezMiranda, Consumption of diets with different type of fat influences triacylglycerols-rich lipoproteins particle number and size during the postprandial state, Nutr. Metab. Cardiovasc.

T

Dis. NMCD, 21 (2011) 39–45.

RI P

[39] I. López-Soldado, M. Avella, K.M. Botham, Differential influence of different dietary fatty acids on very low-density lipoprotein secretion when delivered to hepatocytes in chylomicron remnants, Metabolism., 58 (2009) 186–95.

SC

[40] T.A. Jacobson, M.K. Ito, K.C. Maki, C.E. Orringer, H.E. Bays, P.H. Jones, J.M. McKenney, S.M. Grundy, E.A. Gill, R.A. Wild, D.P. Wilson, W.V. Brown, National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 - executive

NU

summary, J. Clin. Lipidol., 8 (2014) 473–488.

[41] N.J. Stone, J.G. Robinson, A.H. Lichtenstein, C.N. Bairey Merz, C.B. Blum, R.H. Eckel, A.C.

MA

Goldberg, D. Gordon, D. Levy, D.M. Lloyd-Jones, P. McBride, J.S. Schwartz, S.T. Shero, S.C. Smith, K. Watson, P.W.F. Wilson, American College of Cardiology/American Heart Association Task Force on Practice Guidelines, 2013 ACC/AHA guideline on the treatment of blood

ED

cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, J. Am. Coll. Cardiol., 63 (2014) 2889–2934.

PT

[42] H.E. Bays, A.P. Tighe, R. Sadovsky, M.H. Davidson, Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications, Expert Rev.

AC CE

Cardiovasc. Ther., 6 (2008) 391–409. [43] C. Le Jossic-Corcos, C. Gonthier, I. Zaghini, E. Logette, I. Shechter, P. Bournot, Hepatic farnesyl diphosphate synthase expression is suppressed by polyunsaturated fatty acids, Biochem. J., 385 (2005) 787–794. [44] J.D. Horton, Y. Bashmakov, I. Shimomura, H. Shimano, Regulation of sterol regulatory element binding proteins in livers of fasted and refed mice, Proc. Natl. Acad. Sci. U. S. A., 95 (1998) 5987–5992. [45] W.S. Harris, D. Bulchandani, Why do omega-3 fatty acids lower serum triglycerides?, Curr. Opin. Lipidol., 17 (2006) 387–393. [46] Y. Park, W.S. Harris, Omega-3 fatty acid supplementation accelerates chylomicron triglyceride clearance, J. Lipid Res., 44 (2003) 455–63. [47] M.H. Davidson, Omega-3 fatty acids: new insights into the pharmacology and biology of docosahexaenoic acid, docosapentaenoic acid, and eicosapentaenoic acid, Curr. Opin. Lipidol., 24 (2013) 467–474. [48] E.M.M. Ooi, T.W.K. Ng, G.F. Watts, P.H.R. Barrett, Dietary fatty acids and lipoprotein metabolism: new insights and updates, Curr. Opin. Lipidol., 24 (2013) 192–197.

ACCEPTED MANUSCRIPT [49] J.E. Hunter, J. Zhang, P.M. Kris-Etherton, Cardiovascular disease risk of dietary stearic acid compared with trans , other saturated , and unsaturated fatty acids : a systematic review 1 – 4, Am J Clin Nutr Am. Soc. Nutr., 91 (2010) 46–63. [50] T.A.B. Sanders, A. Filippou, S.E. Berry, S. Baumgartner, R.P. Mensink, Palmitic acid in the sn-2

T

position of triacylglycerols acutely influences postprandial lipid metabolism, Am. J. Clin. Nutr.,

RI P

94 (2011) 1433–1441.

[51] L. Hooper, C.D. Summerbell, R. Thompson, D. Sills, F.G. Roberts, H.J. Moore, G. Davey Smith, Reduced or modified dietary fat for preventing cardiovascular disease, Cochrane Database

SC

Syst. Rev., 5 (2012) CD002137.

[52] T.A. Mori, Dietary n-3 PUFA and CVD: a review of the evidence, Proc. Nutr. Soc., 73 (2014) 57–64.

NU

[53] T.A. Mori, R.J. Woodman, The independent effects of eicosapentaenoic acid and docosahexaenoic acid on cardiovascular risk factors in humans, Curr. Opin. Clin. Nutr. Metab.

MA

Care, 9 (2006) 95–104.

[54] T.A. Mori, G.F. Watts, V. Burke, E. Hilme, I.B. Puddey, L.J. Beilin, Differential effects of eicosapentaenoic acid and docosahexaenoic acid on vascular reactivity of the forearm

ED

microcirculation in hyperlipidemic, overweight men, Circulation, 102 (2000) 1264–1269. [55] T.A. Mori TA, V. Burke, L.J. Beilin, Dietary fats and blood pressure, in: Lip GYH, Hall JE (Ed.), Compr. Hypertens., Elsevier, Philadelphia, USA, 2007: pp. 77–88.

PT

[56] S. Khalesi, C. Irwin, M. Schubert, Flaxseed consumption may reduce blood pressure: a systematic review and meta-analysis of controlled trials, J. Nutr., 145 (2015) 758–765.

AC CE

[57] T. Psaltopoulou, A. Naska, P. Orfanos, D. Trichopoulos, T. Mountokalakis, A. Trichopoulou, Olive oil, the Mediterranean diet, and arterial blood pressure: the Greek European Prospective Investigation into Cancer and Nutrition (EPIC) study, Am. J. Clin. Nutr., 80 (2004) 1012–8. [58] A. Alonso, C. de la Fuente, A.M. Martín-Arnau, J. de Irala, J.A. Martínez, M.A. MartínezGonzález, Fruit and vegetable consumption is inversely associated with blood pressure in a Mediterranean population with a high vegetable-fat intake: the Seguimiento Universidad de Navarra (SUN) Study, Br. J. Nutr., 92 (2004) 311–319. [59] V. Ruíz-Gutiérrez, F.J. Muriana, A. Guerrero, A.M. Cert, J. Villar, Plasma lipids, erythrocyte membrane lipids and blood pressure of hypertensive women after ingestion of dietary oleic acid from two different sources, J. Hypertens., 14 (1996) 1483–1490. [60] J.S. Perona, J. Cañizares, E. Montero, J.M. Sánchez-Domínguez, A. Catalá, V. Ruiz-Gutiérrez, Virgin olive oil reduces blood pressure in hypertensive elderly subjects, Clin. Nutr. Edinb. Scotl., 23 (2004) 1113–1121. [61] I. Bondia-Pons, H. Schröder, M.I. Covas, A.I. Castellote, J. Kaikkonen, H.E. Poulsen, A.V. Gaddi, A. Machowetz, H. Kiesewetter, M.C. López-Sabater, Moderate consumption of olive oil by healthy European men reduces systolic blood pressure in non-Mediterranean participants, J. Nutr., 137 (2007) 84–87.

ACCEPTED MANUSCRIPT [62] K.L. Tuck, P.J. Hayball, Major phenolic compounds in olive oil: metabolism and health effects, J. Nutr. Biochem., 13 (2002) 636–644. [63] F. Visioli, G. Bellomo, C. Galli, Free radical-scavenging properties of olive oil polyphenols, Biochem. Biophys. Res. Commun., 247 (1998) 60–4.

T

[64] I. Jialal, S. Devaraj, N. Kaul, The effect of alpha-tocopherol on monocyte proatherogenic

RI P

activity, J. Nutr., 131 (2001) 389S–94S.

[65] D. Wu, M.G. Hayek, S. Meydani, Vitamin E and macrophage cyclooxygenase regulation in the aged, J. Nutr., 131 (2001) 382S–8S.

SC

[66] C.D. Hohmann, H. Cramer, A. Michalsen, C. Kessler, N. Steckhan, K. Choi, G. Dobos, Effects of high phenolic olive oil on cardiovascular risk factors: A systematic review and meta-analysis, Phytomedicine Int. J. Phytother. Phytopharm., 22 (2015) 631–640.

NU

[67] M. Navab, G.M. Anantharamaiah, S.T. Reddy, B.J. Van Lenten, A.M. Fogelman, HDL as a biomarker, potential therapeutic target, and therapy, Diabetes, 58 (2009) 2711–2717.

MA

[68] L. Perségol, B. Vergès, M. Foissac, P. Gambert, L. Duvillard, Inability of HDL from type 2 diabetic patients to counteract the inhibitory effect of oxidised LDL on endothelium-dependent vasorelaxation, Diabetologia, 49 (2006) 1380–1386.

ED

[69] F.H. Mattson, S.M. Grundy, Comparison of effects of dietary saturated, monounsaturated, and polyunsaturated fatty acids on plasma lipids and lipoproteins in man, J. Lipid Res., 26 (1985) 194–202.

PT

[70] M. Rosenblat, N. Volkova, R. Coleman, Y. Almagor, M. Aviram, Antiatherogenicity of extra virgin olive oil and its enrichment with green tea polyphenols in the atherosclerotic apolipoprotein-E523.

AC CE

deficient mice: enhanced macrophage cholesterol efflux, J. Nutr. Biochem., 19 (2008) 514– [71] E.A. Miles, F.A. Wallace, P.C. Calder, An olive oil-rich diet reduces scavenger receptor mRNA in murine macrophages, Br. J. Nutr., 85 (2001) 185–191. [72] A. Andreoli, S. Lauro, N. Di Daniele, R. Sorge, M. Celi, S.L. Volpe, Effect of a moderately hypoenergetic Mediterranean diet and exercise program on body cell mass and cardiovascular risk factors in obese women, Eur. J. Clin. Nutr., 62 (2008) 892–897. [73] D. Mezzano, F. Leighton, Haemostatic cardiovascular risk factors: differential effects of red wine and diet on healthy young, Pathophysiol. Haemost. Thromb., 33 (2003) 472–478. [74] T.A. Jacobson, S.B. Glickstein, J.D. Rowe, P.N. Soni, Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: a review, J. Clin. Lipidol., 6 (2012) 5–18. [75] M.Y. Wei, T.A. Jacobson, Effects of eicosapentaenoic acid versus docosahexaenoic acid on serum lipids: a systematic review and meta-analysis, Curr. Atheroscler. Rep., 13 (2011) 474– 483. [76] R. Clarke, C. Frost, R. Collins, P. Appleby, R. Peto, Dietary lipids and blood cholesterol: quantitative meta-analysis of metabolic ward studies, BMJ, 314 (1997) 112–117.

ACCEPTED MANUSCRIPT [77] C. Beysen, F. Karpe, B.A. Fielding, A. Clark, J.C. Levy, K.N. Frayn, Interaction between specific fatty acids, GLP-1 and insulin secretion in humans, Diabetologia, 45 (2002) 1533–1541. [78] S. Lopez, B. Bermudez, A. Ortega, L.M. Varela, Y.M. Pacheco, J. Villar, R. Abia, F.J.G. Muriana, Effects of meals rich in either monounsaturated or saturated fat on lipid concentrations and on

T

insulin secretion and action in subjects with high fasting triglyceride concentrations, Am. J. Clin.

RI P

Nutr., 93 (2011) 494–499.

[79] M. Gaster, A.C. Rustan, H. Beck-Nielsen, Differential utilization of saturated palmitate and unsaturated oleate: evidence from cultured myotubes, Diabetes, 54 (2005) 648–656.

SC

[80] F. Pérez-Jiménez, J. López-Miranda, M.D. Pinillos, P. Gómez, E. Paz-Rojas, P. Montilla, C. Marín, M.J. Velasco, A. Blanco-Molina, J.A. Jiménez Perepérez, J.M. Ordovás, A Mediterranean and a high-carbohydrate diet improve glucose metabolism in healthy young

NU

persons, Diabetologia, 44 (2001) 2038–2043.

[81] A.C. Tierney, J. McMonagle, D.I. Shaw, H.L. Gulseth, O. Helal, W.H.M. Saris, J.A. Paniagua, I.

MA

Gołąbek-Leszczyñska, C. Defoort, C.M. Williams, B. Karsltröm, B. Vessby, A. Dembinska-Kiec, J. López-Miranda, E.E. Blaak, C.A. Drevon, M.J. Gibney, J.A. Lovegrove, H.M. Roche, Effects of dietary fat modification on insulin sensitivity and on other risk factors of the metabolic

ED

syndrome--LIPGENE: a European randomized dietary intervention study, Int. J. Obes. 2005, 35 (2011) 800–809.

[82] M.D. Ivorra, M. Paya, A. Villar, Effect of beta-sitosterol-3-beta-D-glucoside on insulin secretion

PT

in vivo in diabetic rats and in vitro in isolated rat islets of Langerhans, Pharm., 45 (1990) 271– 273.

AC CE

[83] J.W. Chai, S.-L. Lim, M.S. Kanthimathi, U.R. Kuppusamy, Gene regulation in β-sitosterolmediated stimulation of adipogenesis, glucose uptake, and lipid mobilization in rat primary adipocytes, Genes Nutr., 6 (2011) 181–188. [84] X. Shen, Q. Tang, J. Wu, Y. Feng, J. Huang, W. Cai, Effect of vitamin E supplementation on oxidative stress in a rat model of diet-induced obesity, Int. J. Vitam. Nutr. Res. Int. Z. Für Vitam.- Ernährungsforschung J. Int. Vitaminol. Nutr., 79 (2009) 255–263. [85] L.I. Somova, F.O. Shode, M. Mipando, Cardiotonic and antidysrhythmic effects of oleanolic and ursolic acids, methyl maslinate and uvaol, Phytomedicine Int. J. Phytother. Phytopharm., 11 (2004) 121–9. [86] X. Wang, Y.L. Li, H. Wu, J.Z. Liu, J.X. Hu, N. Liao, J. Peng, P.P. Cao, X. Liang, C.X. Hai, Antidiabetic effect of oleanolic acid: a promising use of a traditional pharmacological agent, Phytother. Res. PTR, 25 (2011) 1031–1040. [87] K. Hamden, N. Allouche, M. Damak, A. Elfeki, Hypoglycemic and antioxidant effects of phenolic extracts and purified hydroxytyrosol from olive mill waste in vitro and in rats, Chem. Biol. Interact., 180 (2009) 421–432. [88] K.F. Petersen, G.I. Shulman, Etiology of insulin resistance, Am. J. Med., 119 (2006) S10-16.

ACCEPTED MANUSCRIPT [89] R. Meshkani, K. Adeli, Hepatic insulin resistance, metabolic syndrome and cardiovascular disease, Clin. Biochem., 42 (2009) 1331–1346. [90] M. Clemente-Postigo, M.I. Queipo-Ortuño, D. Fernandez-Garcia, R. Gomez-Huelgas, F.J. Tinahones, F. Cardona, Adipose tissue gene expression of factors related to lipid processing in

T

obesity, PloS One, 6 (2011) e24783.

RI P

[91] K.N. Frayn, C.M. Williams, P. Arner, Are increased plasma non-esterified fatty acid concentrations a risk marker for coronary heart disease and other chronic diseases?, Clin. Sci. Lond. Engl. 1979, 90 (1996) 243–253.

reevaluation, Diabetes, 60 (2011) 2441–2449.

SC

[92] F. Karpe, J.R. Dickmann, K.N. Frayn, Fatty acids, obesity, and insulin resistance: time for a

[93] N.F. Wiernsperger, Membrane physiology as a basis for the cellular effects of metformin in

NU

insulin resistance and diabetes, Diabetes Metab., 25 (1999) 110–127. [94] A.G. Lee, Lipids and their effects on membrane proteins: evidence against a role for fluidity,

MA

Prog. Lipid Res., 30 (1991) 323–348.

[95] O. Nadiv, M. Shinitzky, H. Manu, D. Hecht, C.T. Roberts, D. LeRoith, Y. Zick, Elevated protein tyrosine phosphatase activity and increased membrane viscosity are associated with impaired

ED

activation of the insulin receptor kinase in old rats, Biochem. J., 298 ( Pt 2) (1994) 443–450. [96] D.A. Pan, S. Lillioja, M.R. Milner, A.D. Kriketos, L.A. Baur, C. Bogardus, L.H. Storlien, Skeletal

96 (1995) 2802–2808.

PT

muscle membrane lipid composition is related to adiposity and insulin action, J. Clin. Invest., [97] N. Zeghari, H. Vidal, M. Younsi, O. Ziegler, P. Drouin, M. Donner, Adipocyte membrane

AC CE

phospholipids and PPAR-gamma expression in obese women: relationship to hyperinsulinemia, Am. J. Physiol. Endocrinol. Metab., 279 (2000) E736-743. [98] M. Younsi, D. Quilliot, N. Al-Makdissy, I. Delbachian, P. Drouin, M. Donner, O. Ziegler, Erythrocyte membrane phospholipid composition is related to hyperinsulinemia in obese nondiabetic women: Effects of weight loss, Metabolism., 51 (2002) 1261–1268. [99] K. Simons, D. Toomre, Lipid rafts and signal transduction, Nat. Rev. Mol. Cell Biol., 1 (2000) 31–39. [100]

T. Okamoto, A. Schlegel, P.E. Scherer, M.P. Lisanti, Caveolins, a family of scaffolding

proteins for organizing “preassembled signaling complexes” at the plasma membrane, J. Biol. Chem., 273 (1998) 5419–5422. [101]

F.H. Nystrom, H. Chen, L.N. Cong, Y. Li, M.J. Quon, Caveolin-1 interacts with the insulin

receptor and can differentially modulate insulin signaling in transfected Cos-7 cells and rat adipose cells, Mol. Endocrinol. Baltim. Md, 13 (1999) 2013–2024. [102]

M. Hahn-Obercyger, L. Graeve, Z. Madar, A high-cholesterol diet increases the association

between caveolae and insulin receptors in rat liver, J. Lipid Res., 50 (2009) 98–107. [103]

E. Ikonen, S. Vainio, Lipid microdomains and insulin resistance: is there a connection?, Sci.

STKE Signal Transduct. Knowl. Environ., 2005 (2005) pe3.

ACCEPTED MANUSCRIPT [104]

R.T. Watson, S. Shigematsu, S.H. Chiang, S. Mora, M. Kanzaki, I.G. Macara, A.R. Saltiel,

J.E. Pessin, Lipid raft microdomain compartmentalization of TC10 is required for insulin signaling and GLUT4 translocation, J. Cell Biol., 154 (2001) 829–840. [105]

O. Gunes, E. Tascilar, E. Sertoglu, A. Tas, M.A. Serdar, G. Kaya, H. Kayadibi, O. Ozcan,

[106]

RI P

obese adolescents, Chem. Phys. Lipids, 184 (2014) 69–75.

T

Associations between erythrocyte membrane fatty acid compositions and insulin resistance in T. Thorseng, D.R. Witte, D. Vistisen, K. Borch-Johnsen, P. Bjerregaard, M.E. Jørgensen,

The association between n-3 fatty acids in erythrocyte membranes and insulin resistance: the

[107]

SC

Inuit Health in Transition Study, Int. J. Circumpolar Health, 68 (2009) 327–336. F. Barceló, J.S. Perona, J. Prades, S.S. Funari, E. Gomez-Gracia, M. Conde, R. Estruch, V.

Ruiz-Gutiérrez, Mediterranean-style diet effect on the structural properties of the erythrocyte

NU

cell membrane of hypertensive patients: the Prevencion con Dieta Mediterranea Study, Hypertens. Dallas Tex 1979, 54 (2009) 1143–1150.

I. Seres, G. Fóris, Z. Varga, B. Kosztáczky, A. Kassai, Z. Balogh, P. Fülöp, G. Paragh, The

MA

[108]

association between angiotensin II-induced free radical generation and membrane fluidity in neutrophils of patients with metabolic syndrome, J. Membr. Biol., 214 (2006) 91–98. A.G. Lee, How lipids affect the activities of integral membrane proteins, Biochim. Biophys.

Acta, 1666 (2004) 62–87. [110]

ED

[109]

K. Tsuda, Y. Kinoshita, I. Nishio, Y. Masuyama, Hyperinsulinemia is a determinant of

PT

membrane fluidity of erythrocytes in essential hypertension, Am. J. Hypertens., 14 (2001) 419– 423.

E. Simon, J.L. Paul, V. Atger, A. Simon, N. Moatti, Erythrocyte antioxidant status in

AC CE

[111]

asymptomatic hypercholesterolemic men, Atherosclerosis, 138 (1998) 375–381. [112]

A.R. Saltiel, C.R. Kahn, Insulin signalling and the regulation of glucose and lipid

metabolism, Nature, 414 (2001) 799–806. [113]

U.N. Das, A defect in the activity of Delta6 and Delta5 desaturases may be a factor

predisposing to the development of insulin resistance syndrome, Prostaglandins Leukot. Essent. Fatty Acids, 72 (2005) 343–350. [114]

L.H. Storlien, D.A. Pan, A.D. Kriketos, J. O’Connor, I.D. Caterson, G.J. Cooney, A.B.

Jenkins, L.A. Baur, Skeletal muscle membrane lipids and insulin resistance, Lipids, 31 Suppl (1996) S261-265. [115]

B. Mirnikjoo, S.E. Brown, H.F. Kim, L.B. Marangell, J.D. Sweatt, E.J. Weeber, Protein

kinase inhibition by omega-3 fatty acids, J. Biol. Chem., 276 (2001) 10888–10896. [116]

M. Haag, N.G. Dippenaar, Dietary fats, fatty acids and insulin resistance: short review of a

multifaceted connection, Med. Sci. Monit. Int. Med. J. Exp. Clin. Res., 11 (2005) RA359-367. [117]

R.N.M. Weijers, Lipid composition of cell membranes and its relevance in type 2 diabetes

mellitus, Curr. Diabetes Rev., 8 (2012) 390–400.

ACCEPTED MANUSCRIPT [118]

J.E. Pessin, D.C. Thurmond, J.S. Elmendorf, K.J. Coker, S. Okada, Molecular basis of

insulin-stimulated GLUT4 vesicle trafficking Location! Location! Location!, J. Biol. Chem., 274 (1999) 2593–2596. [119]

W.T. Garvey, L. Maianu, J.A. Hancock, A.M. Golichowski, A. Baron, Gene expression of

T

GLUT4 in skeletal muscle from insulin-resistant patients with obesity, IGT, GDM, and NIDDM, [120]

RI P

Diabetes, 41 (1992) 465–475.

S. Shigematsu, R.T. Watson, A.H. Khan, J.E. Pessin, The adipocyte plasma membrane

caveolin functional/structural organization is necessary for the efficient endocytosis of GLUT4,

[121]

SC

J. Biol. Chem., 278 (2003) 10683–10690.

A. Dresner, D. Laurent, M. Marcucci, M.E. Griffin, S. Dufour, G.W. Cline, L.A. Slezak, D.K.

Andersen, R.S. Hundal, D.L. Rothman, K.F. Petersen, G.I. Shulman, Effects of free fatty acids

NU

on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity, J. Clin. Invest., 103 (1999) 253–259.

S.A. Kliewer, S.S. Sundseth, S.A. Jones, P.J. Brown, G.B. Wisely, C.S. Koble, P. Devchand,

MA

[122]

W. Wahli, T.M. Willson, J.M. Lenhard, J.M. Lehmann, Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors [123]

ED

alpha and gamma, Proc. Natl. Acad. Sci. U. S. A., 94 (1997) 4318–4323. W.J. Park, J.W. Park, A.H. Merrill, J. Storch, Y. Pewzner-Jung, A.H. Futerman, Hepatic fatty

(2014) 1754–1766. [124]

PT

acid uptake is regulated by the sphingolipid acyl chain length, Biochim. Biophys. Acta, 1841 R.W. Schwenk, E. Dirkx, W.A. Coumans, A. Bonen, A. Klip, J.F.C. Glatz, J.J.F.P. Luiken,

AC CE

Requirement for distinct vesicle-associated membrane proteins in insulin- and AMP-activated protein kinase (AMPK)-induced translocation of GLUT4 and CD36 in cultured cardiomyocytes, Diabetologia, 53 (2010) 2209–2219. [125]

A. Ring, S. Le Lay, J. Pohl, P. Verkade, W. Stremmel, Caveolin-1 is required for fatty acid

translocase (FAT/CD36) localization and function at the plasma membrane of mouse embryonic fibroblasts, Biochim. Biophys. Acta, 1761 (2006) 416–423. [126]

C.P. Liang, S. Han, H. Okamoto, R. Carnemolla, I. Tabas, D. Accili, A.R. Tall, Increased

CD36 protein as a response to defective insulin signaling in macrophages, J. Clin. Invest., 113 (2004) 764–773. [127]

E. Dirkx, R.W. Schwenk, J.F.C. Glatz, J.J.F.P. Luiken, G.J.J.M. van Eys, High fat diet

induced diabetic cardiomyopathy, Prostaglandins Leukot. Essent. Fatty Acids, 85 (2011) 219– 225. [128]

K. Nonomura, Y. Arai, H. Mitani, S. Abe-Dohmae, S. Yokoyama, Insulin down-regulates

specific activity of ATP-binding cassette transporter A1 for high density lipoprotein biogenesis through its specific phosphorylation, Atherosclerosis, 216 (2011) 334–341. [129]

A.R. Tall, Cholesterol efflux pathways and other potential mechanisms involved in the

athero-protective effect of high density lipoproteins, J. Intern. Med., 263 (2008) 256–273.

ACCEPTED MANUSCRIPT [130]

N. Wang, D. Lan, W. Chen, F. Matsuura, A.R. Tall, ATP-binding cassette transporters G1

and G4 mediate cellular cholesterol efflux to high-density lipoproteins, Proc. Natl. Acad. Sci. U. S. A., 101 (2004) 9774–9779. [131]

N. Fournier, N. Attia, D. Rousseau-Ralliard, B. Vedie, F. Destaillats, A. Grynberg, J.L. Paul,

T

Deleterious impact of elaidic fatty acid on ABCA1-mediated cholesterol efflux from mouse and [132]

RI P

human macrophages, Biochim. Biophys. Acta - Mol. Cell Biol. Lipids, 1821 (2012) 303–312. R.R. Singaraja, M. Van Eck, N. Bissada, F. Zimetti, H.L. Collins, R.B. Hildebrand, A.

Hayden, L.R. Brunham, M.H. Kang, J.-C. Fruchart, T.J.C. Van Berkel, J.S. Parks, B. Staels,

SC

G.H. Rothblat, C. Fiévet, M.R. Hayden, Both hepatic and extrahepatic ABCA1 have discrete and essential functions in the maintenance of plasma high-density lipoprotein cholesterol levels in vivo, Circulation, 114 (2006) 1301–1309.

J.K. Kruit, N. Wijesekara, C. Westwell-Roper, T. Vanmierlo, W. de Haan, A. Bhattacharjee,

NU

[133]

R. Tang, C.L. Wellington, D. LütJohann, J.D. Johnson, L.R. Brunham, C.B. Verchere, M.R.

MA

Hayden, Loss of both ABCA1 and ABCG1 results in increased disturbances in islet sterol homeostasis, inflammation, and impaired β-cell function, Diabetes, 61 (2012) 659–664. [134]

M. Koseki, A. Matsuyama, K. Nakatani, M. Inagaki, H. Nakaoka, R. Kawase, M. Yuasa-

ED

Kawase, K. Tsubakio-Yamamoto, D. Masuda, J.C. Sandoval, T. Ohama, Y. Nakagawa-Toyama, F. Matsuura, M. Nishida, M. Ishigami, K. Hirano, N. Sakane, Y. Kumon, T. Suehiro, T. Nakamura, et al., Impaired insulin secretion in four Tangier disease patients with ABCA1 [135]

PT

mutations, J. Atheroscler. Thromb., 16 (2009) 292–296. M. Liu, S. Chung, G.S. Shelness, J.S. Parks, Hepatic ABCA1 and VLDL triglyceride

[136]

AC CE

production, Biochim. Biophys. Acta, 1821 (2012) 770–777. S. Stratford, D.B. DeWald, S.A. Summers, Ceramide dissociates 3’-phosphoinositide

production from pleckstrin homology domain translocation, Biochem. J., 354 (2001) 359–368. [137]

J.R. Zierath, K.L. Houseknecht, L. Gnudi, B.B. Kahn, High-fat feeding impairs insulin-

stimulated GLUT4 recruitment via an early insulin-signaling defect, Diabetes, 46 (1997) 215– 223. [138]

D.M. Ouwens, M. Diamant, M. Fodor, D.D.J. Habets, M.M. a. L. Pelsers, M. El Hasnaoui,

Z.C. Dang, C.E. van den Brom, R. Vlasblom, A. Rietdijk, C. Boer, S.L.M. Coort, J.F.C. Glatz, J.J.F.P. Luiken, Cardiac contractile dysfunction in insulin-resistant rats fed a high-fat diet is associated with elevated CD36-mediated fatty acid uptake and esterification, Diabetologia, 50 (2007) 1938–1948. [139]

J.F.C. Glatz, J.J.F.P. Luiken, A. Bonen, Membrane fatty acid transporters as regulators of

lipid metabolism: implications for metabolic disease, Physiol. Rev., 90 (2010) 367–417. [140]

Z. Li, H. Zhang, J. Liu, C.-P. Liang, Y. Li, Y. Li, G. Teitelman, T. Beyer, H.H. Bui, D. a Peake,

Y. Zhang, P.E. Sanders, M.-S. Kuo, T.-S. Park, G. Cao, X.-C. Jiang, Reducing plasma membrane sphingomyelin increases insulin sensitivity, Mol. Cell. Biol., 31 (2011) 4205–18.

ACCEPTED MANUSCRIPT [141]

J. Sanchez-Wandelmer, A. Davalos, E. Herrera, M. Giera, S. Cano, G. de la Peña, M. A.

Lasuncion, R. Busto, Inhibition of cholesterol biosynthesis disrupts lipid raft/caveolae and affects insulin receptor activation in 3T3-L1 preadipocytes, Biochim. Biophys. Acta Biomembr., 1788 (2009) 1731–1739. J.S. Perona, O. Vögler, J.M. Sánchez-Domínguez, E. Montero, P.V. Escribá, V. Ruiz-

T

[142]

RI P

Gutierrez, Consumption of virgin olive oil influences membrane lipid composition and regulates intracellular signaling in elderly adults with type 2 diabetes mellitus, J. Gerontol. A. Biol. Sci. Med. Sci., 62 (2007) 256–263.

G. Riccardi, R. Giacco, A.A. Rivellese, Dietary fat, insulin sensitivity and the metabolic

SC

[143]

syndrome, Clin. Nutr. Edinb. Scotl., 23 (2004) 447–456. [144]

M. Aoun, F. Michel, G. Fouret, A. Schlernitzauer, V. Ollendorff, C. Wrutniak-Cabello, J.-P.

NU

Cristol, M.-A. Carbonneau, C. Coudray, C. Feillet-Coudray, A grape polyphenol extract modulates muscle membrane fatty acid composition and lipid metabolism in high-fat-high[145]

MA

sucrose diet-fed rats, Br. J. Nutr., 106 (2011) 491–501.

A. Chabowski, M. Zendzian-Piotrowska, K. Konstantynowicz, W. Pankiewicz, A. Miklosz,

B. Lukaszuk, J. Gorski, Fatty acid transporters involved in the palmitate and oleate induced [146]

ED

insulin resistance in primary rat hepatocytes, Acta Physiol., 207 (2013) 346–357. M. Ryan, D. McInerney, D. Owens, P. Collins, A. Johnson, G.H. Tomkin, Diabetes and the

Mediterranean diet: a beneficial effect of oleic acid on insulin sensitivity, adipocyte glucose (2000) 85–91.

R. Alemany, J.S. Perona, J.M. Sánchez-Dominguez, E. Montero, J. Cañizares, R. Bressani,

AC CE

[147]

PT

transport and endothelium-dependent vasoreactivity, QJM Mon. J. Assoc. Physicians, 93

P.V. Escribá, V. Ruiz-Gutierrez, G protein-coupled receptor systems and their lipid environment in health disorders during aging, Biochim. Biophys. Acta, 1768 (2007) 964–975. [148]

R. Alemany, M.A. Navarro, O. Vögler, J.S. Perona, J. Osada, V. Ruiz-Gutiérrez, Olive oils

modulate fatty acid content and signaling protein expression in apolipoprotein E knockout mice brain, Lipids, 45 (2010) 53–61. [149]

P.V. Escribá, J.M. Sánchez-Dominguez, R. Alemany, J.S. Perona, V. Ruiz-Gutiérrez,

Alteration of lipids, G proteins, and PKC in cell membranes of elderly hypertensives, Hypertension, 41 (2003) 176–182. [150]

A.M. Dorrance, D. Graham, R.C. Webb, R. Fraser, A. Dominiczak, Increased membrane

sphingomyelin and arachidonic acid in stroke-prone spontaneously hypertensive rats, Am. J. Hypertens., 14 (2001) 1149–1153. [151]

S.J. Slater, M.B. Kelly, F.J. Taddeo, C. Ho, E. Rubin, C.D. Stubbs, The modulation of protein

kinase C activity by membrane lipid bilayer structure, J. Biol. Chem., 269 (1994) 4866–4871. [152]

E. Peyron-Caso, S. Fluteau-Nadler, M. Kabir, M. Guerre-Millo, A. Quignard-Boulangé, G.

Slama, S.W. Rizkalla, Regulation of glucose transport and transporter 4 (GLUT-4) in muscle

ACCEPTED MANUSCRIPT and adipocytes of sucrose-fed rats: effects of N-3 poly- and monounsaturated fatty acids, Horm. Metab. Res. Horm. Stoffwechselforschung Horm. Métabolisme, 34 (2002) 360–366. [153]

O.J. Rimoldi, G.S. Finarelli, R.R. Brenner, Effects of diabetes and insulin on hepatic delta6

desaturase gene expression, Biochem. Biophys. Res. Commun., 283 (2001) 323–326. N. Guelzim, J.-F. Huneau, V. Mathé, S. Tesseraud, J. Mourot, N. Simon, D. Hermier, N-3

T

[154]

RI P

fatty acids improve body composition and insulin sensitivity during energy restriction in the rat, Prostaglandins Leukot. Essent. Fatty Acids, 91 (2014) 203–211. [155]

M. Kunesová, R. Braunerová, P. Hlavatý, E. Tvrzická, B. Stanková, J. Skrha, J. Hilgertová,

SC

M. Hill, J. Kopecký, M. Wagenknecht, V. Hainer, M. Matoulek, J. Parízková, A. Zák, S. Svacina, The influence of n-3 polyunsaturated fatty acids and very low calorie diet during a short-term weight reducing regimen on weight loss and serum fatty acid composition in severely obese [156]

NU

women, Physiol. Res. Acad. Sci. Bohemoslov., 55 (2006) 63–72. M. Fickova, P. Hubert, G. Crémel, C. Leray, Dietary (n-3) and (n-6) polyunsaturated fatty

MA

acids rapidly modify fatty acid composition and insulin effects in rat adipocytes, J. Nutr., 128 (1998) 512–519. [157]

L. Nagy, T. Atkinson, K. Mecklinggill, Feeding docosahexaenoic acid impairs hormonal

[158]

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control of glucose transport in rat adipocytes, J. Nutr. Biochem., 7 (1996) 356–363. A. Doublet, V. Robert, B. Vedie, D. Rousseau-Ralliard, A. Reboulleau, A. Grynberg, J.-L.

Paul, N. Fournier, Contrasting effects of arachidonic acid and docosahexaenoic acid

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membrane incorporation into cardiomyocytes on free cholesterol turnover, Biochim. Biophys. Acta, 1842 (2014) 1413–1421.

W. Kim, N.A. Khan, D.N. McMurray, I.A. Prior, N. Wang, R.S. Chapkin, Regulatory activity

AC CE

[159]

of polyunsaturated fatty acids in T-cell signaling, Prog. Lipid Res., 49 (2010) 250–261. [160]

N. Fournier, S. Tardivel, J.F. Benoist, B. Vedie, D. Rousseau-Ralliard, M. Nowak, F. Allaoui,

J.L. Paul, Eicosapentaenoic acid membrane incorporation impairs ABCA1-dependent cholesterol efflux via a protein kinase A signaling pathway in primary human macrophages, Biochim. Biophys. Acta, 1861 (2016) 331–341. [161]

E.J. Meuillet, V. Leray, P. Hubert, C. Leray, G. Cremel, Incorporation of exogenous lipids

modulates insulin signaling in the hepatoma cell line, HepG2, Biochim. Biophys. Acta - Mol. Basis Dis., 1454 (1999) 38–48. [162]

A. Zarubica, D. Trompier, G. Chimini, ABCA1, from pathology to membrane function, Pflüg.

Arch. Eur. J. Physiol., 453 (2007) 569–579. [163]

S.L. Niu, D.C. Mitchell, B.J. Litman, Trans fatty acid derived phospholipids show increased

membrane cholesterol and reduced receptor activation as compared to their cis analogs, Biochemistry (Mosc.), 44 (2005) 4458–4465. Figure 1. Influence of unsaturation degree of phospholipid fatty acids on cell membrane fluidity. Saturated fatty acids result in rigid membrane domains (A, stearic acid, 18:0), while

ACCEPTED MANUSCRIPT monounsaturated (B, oleic acid, 18:1 n-9) and polyunsaturated (C, linoleic acid, 18:2 n-6) fatty acids occupy more space leading to mode fluid domains. Figure 2. Schematic diagram of the pathways associated with membrane proteins related to

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insulin activation. Upon insulin arrival to the target tissue the insulin receptor substrate (IRS) is

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bound to the receptor (IR), which causes phosphatidylinositol-3 kinase (PI3K) activation. After subsequent phosphorylations, protein kinase C and B/AKT (PKB/AKT) are activated, which regulate different pathways related to lipid and glucose metabolism. PKC phosphorylates

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intracelluar vesicles containing the glucose transporter 4 (GLUT4) causing its translocation to the membrane and allowing glucose uptake to the cell. PKB/AKT inhibits glycogen synthase kinase 3 (GSK3), which causes the inhibition of glycogen synthase limiting glycogen synthesis. In addition

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PBK/AKT, via protein kinase A (PKA), activates hormone sensitive lipase (HSL), increasing lipolysis and inhibits acetyl-CoA carboxylase (ACC), which is involved in fatty acid synthesis. PI3K

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also activates CD36 translocation to the membrane, which facilitates fatty acid uptake to the cell and eventually triglyceride storage. Finally, in insulin resistance PI3K is also involved in ATPbinding cassette transporter (ABCA-1) down-regulation and reduced cholesterol efflux from the

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cells vía HDL-cholesterol formation.

Figure 3. Schematic diagram of the pathways activated by fatty acid uptake in insulin

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targeted tissues. Phosphatidylinositol-3 kinase (PI3K) activation after binding of the insulin receptor substrate (IRS) to the insulin receptor (IR) leads to protein kinase C and B/AKT

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(PKB/AKT) activation. This kinase activates CD36 translocation to the membrane, which facilitates fatty acid uptake. Once in the cytosol, fatty acids are transported by the cytoplasmic fatty acidbinding protein (cFABP) and can be used for b-oxidation or stored in the form of triglycerides (TG). In addition, fatty acids can also be transformed into diglycerides and ceramides, which participate in the regulation of fatty acid uptake by inhibiting PKB/AKT and, thus, impairing CD36 translocation to the membrane.

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ACCEPTED MANUSCRIPT Highlights The metabolic syndrome is a cluster of conditions related to insulin resistance.

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Insulin resistance is cause and consequence of impaired membrane lipid composition.

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Dietary fatty acids can modulate membrane lipid composition and function.

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Restoration of lipid composition of membrane microdomains improves its fluidity.

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Changes in membrane lipid composition improve markers of metabolic syndrome.

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