- Email: [email protected]
Novel aspects of postprandial lipemia in relation to atherosclerosis
Atherosclerosis Supplements 9 (2008) 39–44
Novel aspects of postprandial lipemia in relation to atherosclerosis A. Alipour, J.W.F. Elte, H.C.T. van Zaanen, A.P. Rietveld, M. Castro Cabezas ∗ Department of Internal Medicine, Sint Franciscus Gasthuis, Rotterdam, The Netherlands Received 30 January 2008; received in revised form 22 February 2008; accepted 13 May 2008
Abstract Postprandial hyperlipidemia is considered to be a substantial risk factor for atherosclerosis. Interestingly, this concept has never been supported by randomized clinical trials. The difficulty lies in the fact that most interventions aimed to reduce postprandial lipemia, will also affect LDL-C levels. The atherogenic mechanisms of postprandial lipids and lipoproteins can be divided into direct lipoprotein-mediated and indirect effects; the latter, in part, by inducing an inflammatory state. Elevations in postprandial triglycerides (TG) have been related to the increased expression of postprandial leukocyte activation markers, up-regulation of pro-inflammatory genes in endothelial cells and involvement of the complement system. This set of events is part of the postprandial inflammatory response, which is one of the recently identified potential pro-atherogenic mechanisms of postprandial lipemia. Especially, complement component 3 levels show a close correlation with postprandial lipemia and are also important determinants of the metabolic syndrome. In clinical practice, fasting TG are frequently used as reflections of postprandial lipemia due to the close correlation between the two. The use of serial capillary measurements in an out-ofhospital situation is an alternative for oral fat loading tests. Daylong TG profiles reflect postprandial lipemia and are increased in conditions like the metabolic syndrome, type 2 diabetes and atherosclerosis. Studies are needed to elucidate the role of postprandial inflammation in atherogenesis and to find new methods in order to reduce selectively the postprandial inflammatory response. Future studies are needed to find new methods in order to reduce selectively the postprandial inflammatory response. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Triglyceride-rich lipoproteins; Inflammation; Leukocytes; Complement
1. Introduction Disturbances of triglyceride (TG) metabolism are closely associated to atherosclerosis [1]. There is a close correlation between fasting and postprandial TG, although inter-individual differences may be high, in part due to differences in insulin sensitivity [2,3]. Subjects with fasting hypertriglyceridemia usually have elevated postprandial lipemia. Patients with obesity, diabetes mellitus and the metabolic syndrome have postprandial hyperlipidemia [4]. One of the proposed mechanisms has been competition Abbreviations: TRL, triglyceride-rich lipoproteins; CAD, coronary artery disease; C3, complement component 3; ASP, acylation stimulating protein; MBL, mannose-binding lectin. ∗ Corresponding author at: Department of Internal Medicine, Sint Franciscus Gasthuis, Center for Diabetes and Vascular Medicine, PO Box 10900, 3004 BA, Rotterdam, The Netherlands. Tel.: +31 10 4617267; fax: +31 10 4612692. E-mail address: [email protected] (M. Castro Cabezas). 1567-5688/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosissup.2008.05.007
between endogenous and exogenous TG-rich lipoproteins (TRLs) at different TG catabolic sites by overproduction of very low-density lipoproteins (VLDL) in the liver, in part due to hepatic insulin resistance. However, also patients with atherosclerosis with and without the metabolic syndrome, even in the presence of normal fasting TG, have postprandial hyperlipidemia [5,6]. Consequently, postprandial hyperlipidemia is a generalized phenomenon in high-risk conditions for atherosclerosis. Recently, inflammatory mechanisms have been associated with postprandial lipemia. These mechanisms include postprandial leukocyte activation, postprandial up-regulation of inflammation-associated genes in the endothelial cells and the activation of the complement system [7–10]. For example, complement component 3 (C3) is a strong determinant of postprandial lipemia and the metabolic syndrome [11], and it responds to treatment with statins [6]. In this paper we will review old and new concepts associated to postprandial lipemia and their role in atherogenesis.
40
A. Alipour et al. / Atherosclerosis Supplements 9 (2008) 39–44
2. Physiology of postprandial TG metabolism In the normal situation fasting TG are transported in the blood mainly in VLDL, containing apoB100 [12]. In the blood, VLDL is converted into VLDL remnants (IDL, intermediate density lipoproteins) by the action of lipoprotein lipase (LPL) attached to endothelial cells [13]. ApoCII present on the surface of VLDL (and chylomicrons) is a necessary co-factor for the hydrolysis of TG by LPL. ApoCIII, also a surface protein on VLDL (and chylomicrons), regulates the hydrolysis of TG by impeding the binding to LPL. In the circulation, VLDL remnants are enriched with apoE, the preferential ligand for the LDL-receptor and the hypothetical remnant receptor. Under physiological conditions IDL is taken up by LDL receptors in the liver where the lipoproteins are degraded and cholesterol is removed from the body by excretion into the bile. Part of IDL is degraded to LDL by the action of a different enzyme localized in the liver sinusoids, hepatic triglyceride lipase (HTGL). In the postprandial period, both VLDL and chylomicrons (with apoB100 and apoB48, respectively, as structural proteins) contribute to postprandial lipemia [12].
3. Epidemiological and observational evidence for the role of postprandial hyperlipidemia in atherosclerosis The concentration of fasting plasma TG is an independent risk factor for atherosclerosis, even in the range previously considered to be normal (below 2.0 mmol/L) [1]. Hypothetical mechanisms leading to atherosclerosis in hypertriglyceridemic subjects comprise exaggerated and prolonged postprandial lipemia with accumulation of atherogenic chylomicron remnants [5,14,15], the generation of small dense low density lipoproteins (LDL), decreased high density lipoprotein (HDL) concentrations and activation of leukocytes and endothelial cells by remnants and fatty acids [7–10]. All these mechanisms may be involved in the postprandial endothelial dysfunction as observed by several investigators [7–9,16], which is closely connected to atherosclerosis. Other processes contributing to endothelial dysfunctions are the generation of reactive oxidative species (ROS) and the formation of oxidized remnant lipoproteins [7,10]. These oxidized remnants are internalized by macrophages, eventually inducing foam cell formation [17]. In individual patient management, single fasting TG measurements are unreliable, with intra-individual coefficients of variation up to 60% [18]. In the Physicians Health Study, plasma TG levels 3–4 h after a meal distinguished better between cases with future myocardial infarction and controls than fasting plasma TG levels [19]. Recently, in a prospective study in healthy US women, it was shown that nonfasting TG levels, strongly and independently, predicted cardiovascular events even after adjustment for levels of total cholesterol and HDL-C and measures of insulin resistance [20]. In another large prospective study in Denmark, elevated
nonfasting TG levels were associated with increased risk of myocardial infarction, ischemic heart disease and death in men and women [21]. Several observational studies demonstrated delayed clearance of TRLs and suggested a direct relationship with the process of atherosclerosis in different groups [4–6,15,22,23].
4. Determinants of postprandial lipemia Many investigators have shown repeatedly that fasting TG is the major determinant of postprandial lipemia [2,3,5,15,23]. Other important parameters associated to postprandial lipemia are LPL and HTGL activities, HDL-C concentrations, apoB, apoE, apoCII and apoCIII. In addition, variables related to insulin sensitivity and the metabolic syndrome like the homeostatic model assessment (HOMA), waist circumference, fat mass and distribution are also closely correlated to the postprandial response [2–4,24]. Furthermore, high liver fat in subjects with nonalcoholic fatty liver disease has also been associated with an increased response of postprandial lipids in plasma, chylomicrons, and VLDL1 [25]. In contrast, the composition of the diet is only a weak determinant of the postprandial TG response [2,3,17,26]. Recently, associations between postprandial lipemia and other variables like the C3 and the acylation stimulating protein (ASP) have been reported. Activation of the complement system results in cleavage of C3, which is central in these pathways [27]. The C3/ASP-system has been recognized as a regulator of adipose tissue fatty acid metabolism [28]. ASP is identical to the desarginated form of the C3 split-product C3a (C3a-desArg), which is immunologically inactive. The C3/ASP pathway stimulates re-esterification of FFA into TG in adipocytes, reduces adipocyte FFA production by inhibiting hormone sensitive lipase and stimulates glucose uptake by adipocytes, fibroblasts and muscle cells [28]. C3 has been associated positively with fasting and postprandial TG, obesity, insulin resistance and the metabolic syndrome. Furthermore, C3 has been recognized as a strong predictor of myocardial infarction and complement activation also plays a role in the induction of tissue damage after myocardial infarction [29]. Macrophages may also activate C3 [30]. Recently, it has been shown that HDL3 from men with established coronary artery disease (CAD), is enriched with C3, suggesting that complement activation can occur by binding to HDL, which acts as an antigen [31] and that HDL may be the carrier of the C3 produced by macrophages in the sub-endothelium. Activation of the complement system leads to triggering of leukocytes, thereby promoting atherosclerosis (Fig. 1). Other factors involved in leukocyte activation are CRP, IL-6 and oxidative stress [29]. Another factor of the innate immune system, which recently has been associated to postprandial lipemia, is mannose-binding lectin (MBL) [32]. MBL is an important activating factor in the lectin pathway of the complement sys-
A. Alipour et al. / Atherosclerosis Supplements 9 (2008) 39–44
Fig. 1. Concept of the initiation of atherosclerosis in the bloodstream by the concerted action of leukocytes and the complement system. Triglyceriderich lipoproteins (TRLs) induce leukocyte activation. These leukocytes can activate the endothelium and induce the expression of cellular adhesion molecules (CAMs) and selectins, facilitating adherence of all leukocytes including lymphocytes. This will lead to adherence of these cells to the endothelium as well as the production of chemoattractants leading to the recruitment and activation of other leukocytes. The activated leukocytes are able to produce reactive oxygen species (ROS), which destabilize atherosclerotic lesions. Monocytes and lymphocytes transmigrate across the endothelial wall. Monocytes residing in the arterial wall differentiate into macrophages. Oxidative modification of LDL and remnants results in a highly atherogenic particle that can easily be taken up by macrophages. The latter can activate endothelial cells resulting in production of CAMs and pro-inflammatory cytokines (IL-6, IL-8 and MCP-1). Defects in the C3/ASP system (alternative pathway) lead to an enhanced flux of hepatic free fatty acids to the liver, which will in turn up-regulate hepatic VLDL secretion. The increase of lipoproteins in the bloodstream activates the classical pathway by CRP and binding of C3 to these lipoproteins (HDL3 ). Within the sub-endothelium the macrophages and foam cells also activate the classical pathway of the complement system. The activation of this pathway will promote leukocyte activation.
tem [27]. The reported frequency of MBL deficiency in the literature ranges from 11.1% to 41.5%. MBL deficiency has been associated to CAD and increased intimia media thickness (IMT) in carotid arteries [33,34]. Altogether, MBL may become an important determinant of atherosclerosis in the population.
41
Recent studies suggest alternative mechanisms. Postprandial TRLs of hyperlipidemic patients, and not of normotriglyceridemic subjects, modulate pro-inflammatory genes in endothelial cells and prolong the reduction of FMD beyond 8 h postprandially [8]. Postprandial and remnant lipoproteins may induce the expression of leukocyte adhesion molecules on the endothelium, facilitating recruitment of inflammatory cells. Activation of only endothelial cells is not sufficient to initiate the process of atherogenesis. Leukocyte activation and binding to the endothelium are obligatory steps [9,35]. A cytokine-controlled sequential up-regulation of selectins and adhesion molecules on activated leukocytes and endothelial cells is necessary. It has been shown that neutrophils increase postprandially with concomitant production of pro-inflammatory cytokines and oxidative stress and that these changes may contribute to endothelial dysfunction [7–10]. In healthy volunteers and in patients with premature atherosclerosis postprandial lipemia has been associated with the up-regulation of leukocyte activation markers [9,10]. Fasting leukocytes of patients with CVD have an increased lipid content when compared to controls and it was suggested that this was due to the uptake of chylomicrons in the bloodstream [36]. Recently, we have shown that apoB binds to neutrophils and monocytes and that postprandially, leukocytes become enriched with meal-derived fatty acids suggesting a direct interaction between lipoproteins and leukocytes by the leukocytes’ uptake of exogenous fatty acids in the bloodstream [37]. Increased residence time of atherogenic lipoproteins in plasma will result in enhanced binding of these particles to the endothelium thereby creating a marginated pool of endothelial bound lipoproteins [38], increasing the level of activation of the endothelial cells which potentially will expose more adhesion molecules on their surface [9,29]. These series of events will ultimately lead to the adhesion of inflammatory cells (especially, monocytes and lymphocytes but potentially also neutrophils) to the activated endothelium. Therefore, we have hypothesized that atherogenesis may start in the blood stream and not in the sub-endothelium as generally considered.
6. Methods to study postprandial lipemia 5. Novel atherogenic mechanisms of postprandial lipemia In the event that the liver is overproducing VLDL particles, like in (central) obesity, the metabolic syndrome, type 2 diabetes and familial combined hyperlipidemia (FCHL) [4,9,12,24], the common catabolic steps for VLDL and chylomicrons become saturated resulting in accumulation of both VLDL and chylomicron remnants. According to the classical concept of atherosclerosis by postprandial lipemia, remnant lipoproteins penetrate the vessel wall and are taken up by monocytes inducing foam cell formation. This may be one of the first steps in atherogenesis.
Several methods have been used to study chylomicron remnant metabolism. One should realize that these particles only represent part of postprandial response and that all lipoprotein factors are involved [12,13]. In line with the above description, both, the intestine and the liver secrete TRLs during the postprandial phase [12]. The methods to study the postprandial period depend on the area of interest. If TG metabolism is evaluated, simple oral fat loading tests may be used. Metabolic ward studies, however, may not provide a realistic impression of the free-living daytime situation and cannot be applied in clinical practice in large populations. Clinically applicable assays may be used to study
42
A. Alipour et al. / Atherosclerosis Supplements 9 (2008) 39–44
apoB48 levels and remnant particles [38]. However, these assays have not been proven to be reliable, cost-effective and time-effective yet [39]. An alternative could be the use of serial capillary measurements in an out-of-hospital situation [2–4,24,26]. Daylong TG profiles are closely related to postprandial lipemia as assessed by standardized oral fat loading tests and can be easily applied in clinical practice for routine screening of populations [3]. Repeated measurements of daylong triglyceridemia are less variable than fasting and postprandial capillary TG in normolipidemic subjects and in subjects with FCHL [18]. Daytime triglyceridemia has been associated with insulin resistance, body composition and diet [2–4,24,26]. Daytime TG profiles distinguish better between normolipidemic patients with CAD and healthy controls matched for age, gender and BMI than other lipid and non-lipid risk factors.
7. Strategies to reduce postprandial lipemia Without any doubt the first intervention should be lifestyle improvement. Weight reduction by lowering dietary energy intake and increased physical activity improves fasting and postprandial plasma lipids, insulin sensitivity, CRP, IL-6 and ASP levels [40]. Furthermore, weight decrease reduces also the progression of atherosclerosis determined by IMT [41]. Reduction of visceral adipose tissue has also been associated with improvement in apolipoprotein B-100 metabolism in obese men [42]. These findings are well in line with our observations that especially the waist circumference is related to diurnal triglyceridemia [2–4,24]. Treatment with fibrates is the first choice in hypertriglyceridemia improving both fasting and postprandial TGs [43]. Ciprofibrate therapy in type 2 diabetics has been shown to improve fasting and postprandial endothelial function, most likely by beneficial effects on TG and HDL metabolism [44]. In combined hyperlipidemia the use of gemfibrozil or fenofibrate decreased postprandial remnant-like particles [45]. It is so far unclear how these effects translate to primary end points in large clinical trials [46–50]. The use of fibrates reduces secondary events in patients with established coronary heart disease with low levels of HDL cholesterol [46,47] and a decrease of the progression of focal coronary atherosclerosis in young survivors of myocardial infarction [48,49]. However, fenofibrate did not reduce significantly the risk of coronary events in patients with type 2 diabetes in the fenofibrate intervention and event lowering in diabetes (FIELD) study [50]. An alternative for fibrates is niacin, which also decreases fasting and postprandial TG concentrations [51]. However, this is not a very popular drug because of its side effects. A different approach to reduce plasma TG concentrations may be improvement of insulin sensitivity by, for example, metformin or the thiazolidinedione derivatives (TZDs). In nondiabetic individuals who were mildly overweight and glucose intolerant, metformin therapy resulted in beneficial
effects in the clearance of postprandial lipoproteins [52]. It has been shown that rosiglitazone improves the metabolism of large TRLs and decreases postprandial FFA concentrations in type 2 diabetes [53]. However, the results of studies on the effects of TZDs on cardiovascular endpoints are inconclusive [54–56]. Although inhibitors of cholesterol synthesis (HMGCoA reductase inhibitors, statins) predominantly reduce LDL cholesterol levels, they also diminish plasma TG concentrations [6,10,12,38,57]. In several studies in humans and in animals, postprandial lipemia was also improved by the use of reductase inhibitors [12,38,58]. Moreover, the use of atorvastatin, with a pronounced effect on plasma TGs [59], during 18 months in patients with stable CAD was as effective as angioplasty and usual care [60]. These effects might be attributed, in part, to the pluripotential effects of statins besides reductions of plasma cholesterol and TG concentrations [61]. Furthermore, atorvastatin has been shown to decrease the postprandial marginated pool of atherogenic lipoproteins in subjects with FCHL [58]. This may represent an additive anti-atherogenic mechanism of treatment with statins that cannot be detected measuring only fasting plasma lipids. In addition, as described above, postprandial leukocyte activation may be an important target to reduce atherogenesis. Unfortunately, statin therapy does not reduce the postprandial increase of leukocyte activation markers in mildly hyperlipidemic patients with premature coronary sclerosis [10]. Future studies are needed to find new methods in order to reduce not only the postprandial lipemia, but also the postprandial inflammation.
8. Conclusions Overproduction of TRLs, characteristic for postprandial lipemia, leads to a complex series of events potentially inducing atherogenesis. These mechanisms can be divided into direct and indirect effects. Direct effects include increased residence time of atherogenic lipoproteins in plasma, resulting in enhanced binding of these particles to the endothelium thereby creating a marginated pool of endothelial cell-bound lipoproteins. The indirect pathway involves inflammatory aspects such as the activation of leukocytes and the endothelium, as well as the activation of the complement system. Inhibiting this pathway should be our next therapeutic goal.
Conflict of interest None.
References [1] Austin MA, Hokanson JE, Edwards KL. Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol 1998;81:7B–12B.
A. Alipour et al. / Atherosclerosis Supplements 9 (2008) 39–44 [2] Van Oostrom AJHHM, Castro Cabezas M, Ribalta J, et al. Diurnal triglyceride profiles in healthy normolipidemic male subjects are associated to insulin sensitivity, body composition and diet. Eur J Clin Invest 2000;30:964–71. [3] Castro Cabezas M, Halkes CJM, Meijssen S, van Oostrom AJHHM, Erkelens DW. Diurnal triglyceride profiles: a novel approach to study triglyceride changes. Atherosclerosis 2001;155:219– 28. [4] Van Wijk JPH, Halkes CJM, Erkelens DW, Castro Cabezas M. Fasting and daytime triglycerides in obesity with and without type 2 diabetes. Metabolism 2003;52:1043–9. [5] Groot PHE, van Stiphout WAHJ, Krauss XH, et al. Postprandial lipoprotein metabolism in normolipidemic men with and without coronary artery disease. Arterioscler Thromb 1991;11:653–62. [6] Halkes CJ, van Dijk H, de Jaegere PP, et al. Postprandial increase of complement component 3 in normolipidemic patients with coronary artery disease: effects of expanded-dose simvastatin. Arterioscler Thromb Vasc Biol 2001;21:1526–30. [7] Van Oostrom AJHHM, Sijmonsma TP, Verseyden C, et al. Postprandial recruitment of neutrophils may contribute to endothelial dysfunction. J Lipid Res 2003;44:576–83. [8] Norata GD, Grigore L, Raselli S, et al. Post-prandial endothelial dysfunction in hypertriglyceridemic subjects: molecular mechanisms and gene expression studies. Atherosclerosis 2007;193:321–7. [9] Alipour A, Elte JWF, Rietveld AP, van Zaanen HCT, Castro Cabezas M. Postprandial inflammation and endothelial dysfunction. Biochem Soc Trans 2007;35(Pt 3):466–9. [10] Van Oostrom AJHHM, Plokker HWM, van Asbeck BS, et al. Effects of rosuvastatin on postprandial leukocytes in mildly hyperlipidemic patients with premature coronary sclerosis. Atherosclerosis 2006;185:331–9. [11] Van Oostrom AJHHM, Alipour A, Plokker HWM, Sniderman AD, Castro Cabezas M. The metabolic syndrome in relation to complement component 3 and postprandial lipemia in patients from an outpatient lipid clinic and healthy volunteers. Atherosclerosis 2007;190:167– 73. [12] Castro Cabezas M, de Bruin TWA, Kock LAW, de Bruin TW. Postprandial apolipoprotein B100 and apo B48 in familial combined hyperlipidemia before and after reduction of fasting plasma triglycerides. Eur J Clin Invest 1994;24:669–78. [13] Karpe F, Tornvall P, Olivecrona T, et al. Composition of human low density lipoprotein: effects of postprandial triglyceride-rich lipoproteins, lipoprotein lipase, hepatic lipase and cholesteryl ester transfer protein. Atherosclerosis 1993;98:33–49. [14] Zilversmit DB. Atherogenesis: a postprandial phenomenon. Circulation 1979;60:473–85. [15] Karpe F, Steiner G, Uffelman K, Olivecrona T, Hamsten A. Postprandial lipoproteins and progression of coronary atherosclerosis. Atherosclerosis 1994;106:83–97. [16] Ceriello A, Taboga C, Tonutti L, et al. Evidence for an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial dysfunction and oxidative stress generation: effects of short-and long-term simvastatin treatment. Circulation 2002;106:1211–8. [17] Bravo E, Napolitano M. Mechanisms involved in chylomicron remnant lipid uptake by macrophages. Biochem Soc Trans 2007;35(Pt 3):459–63. [18] Delawi D, Meijssen S, Castro Cabezas M. Intra-individual variations of fasting plasma lipids, apolipoproteins and postprandial lipemia in familial combined hyperlipidemia compared to controls. Clin Chim Acta 2003;328:139–45. [19] Stampfer MJ, Krauss RM, Ma J, et al. A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. JAMA 1996;276:882–8. [20] Bansal S, Buring JE, Rifai N, et al. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA 2007;298:309–16.
43
[21] Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007;298:299–308. [22] Castro Cabezas M, de Bruin TW, Jansen H, et al. Impaired chylomicron remnant clearance in familial combined hyperlipidemia. Arterioscler Thromb 1993;13:804–14. [23] Patsch JR, Miesenb¨ock G, Patsch W. Relation of triglyceride metabolism and coronary disease. Studies in the postprandial state. Arterioscler Thromb 1992;12:1336–45. [24] Halkes CJM, Castro Cabezas M, van Wijk JPH, Erkelens DW. Gender differences in diurnal triglyceridemia in lean and overweight subjects. Int J Obes 2001;25:1767–74. [25] Matikainen N, M¨antt¨ari S, Westerbacka J, et al. Postprandial lipemia associates with liver fat content. J Clin Endocrinol Metab 2007;92:3052–9. [26] Van Wijk JPH, Castro Cabezas M, Halkes CJM, Erkelens DW. Effects of different nutrient intakes on daytime triacylglycerolemia in healthy, normolipemic, free-living men. Am J Clin Nutr 2001;74:171–8. [27] Walport MJ. Complement; first of two parts. N Engl J Med 2001;344:1058–65. [28] Cianflone K, Xia Z, Chen LY. Critical review of acylation-stimulating protein physiology in humans and rodents. Biochim Biophys Acta 2003;1609:127–43. [29] Van Oostrom AJ, van Wijk J, Castro Cabezas M. Lipaemia, inflammation and atherosclerosis: novel opportunities in the understanding and treatment of atherosclerosis. Drugs 2004;64(Suppl. 2):19–41. [30] Strunk RC, Kunke KS, Giclas PC. Human peripheral blood monocytederived macrophages produce haemolytically active C3 in vitro. Immunology 1983;49:169–74. [31] Vaisar T, Pennathur S, Green PS, et al. Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J Clin Invest 2007;117:746–56. [32] Alipour A, van Oostrom AJHHM, Van Wijk JPH, et al. Deficiency of mannose binding lectin is associated to impaired metabolism of VLDL1 particles despite fasting plasma triglycerides. Circulation 2007;Suppl.:1098. [33] Best LG, Davidson M, North KE, et al. Prospective analysis of mannose-binding lectin genotypes and coronary artery disease in American Indians. Circulation 2004;109:471–5. [34] Madsen HO, Videm V, Svejgaard A, Svennevig JL, Garred P. Association of mannose-binding lectin deficiency with severe atherosclerosis. Lancet 1998;352:959–60. [35] Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999;340:115–26. [36] Tertov VV, Kalenich OS, Orekhov AN. Lipid-laden white blood cells in the circulation of patients with coronary heart disease. Exp Mol Pathol 1992;57:22–8. [37] Alipour A, van Oostrom AJHHM, Izraeljan A, et al. Leukocyte activation by triglyceride-rich lipoproteins. Arterioscler Thromb Vasc Biol 2008;28:792–7 [Epub ahead of print]. [38] Verseyden C, Meijssen S, Castro Cabezas M. Effects of atorvastatin on fasting plasma and marginated apolipoproteins B48 and B100 in large, triglyceride-rich lipoproteins in familial combined hyperlipidemia. J Clin Endocrinol Metab 2004;89:5021–9. [39] Cohn JS. Postprandial lipemia and remnant lipoproteins. Clin Lab Med 2006;26:773–86. [40] Bruun JM, Verdich C, Toubro S, Astrup A, Richelsen B. Association between measures of insulin sensitivity and circulating levels of interleukin-8, interleukin-6 and tumor necrosis factor-alpha. Effect of weight loss in obese men. Eur J Endocrinol 2003;148:535–42. [41] Karason K, Wikstrand J, Sjostrom L, Wendelhag I. Weight loss and progression of early atherosclerosis in the carotid artery: a four-year controlled study of obese subjects. Int J Obes Relat Metab Disord 1999;23:948–56. [42] Riches FM, Watts GF, Hua J, et al. Reduction in visceral adipose tissue is associated with improvement in apolipoprotein B-100 metabolism in obese men. J Clin Endocrinol Metab 1999;84:2854–61.
44
A. Alipour et al. / Atherosclerosis Supplements 9 (2008) 39–44
[43] Fruchart JC, Brewer HB, Leitersdorf E. Consensus for the use of fibrates in the treatment of dyslipoproteinemia and coronary heart disease. Am J Cardiol 1998;81:912–7. [44] Evans M, Anderson RA, Graham J, et al. Ciprofibrate therapy improves endothelial function and reduces postprandial lipemia and oxidative stress in type 2 diabetes mellitus. Circulation 2000;101:1773–9. [45] Ooi TC, Cousins M, Ooi DS, Nakajima K, Edwards AL. Effect of fibrates on postprandial remnant-like particles in patients with combined hyperlipidemia. Atherosclerosis 2004;172:375–82. [46] Syv¨anne M, Nieminen MS, Frick H, et al. Associations between lipoproteins and the progression of coronary and vein-graft atherosclerosis in a controlled trial with gemfibrozil in men with low baseline levels of HDL cholesterol. Circulation 1998;98:1993–9. [47] Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of highdensity lipoprotein cholesterol. N Engl J Med 1999;341:410–8. [48] Ericsson CG, Hamsten A, Nilsson J, et al. Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients. Lancet 1996;347:849–53. [49] Ruotolo G, Ericsson C-G, Tettamanti C, et al. Treatment effect on serum lipoprotein lipids, apolipoproteins and low density lipoprotein particle size and relationships of lipoprotein variables to progression of coronary artery disease in the bezafibrate coronary atherosclerosis intervention trial (BECAIT). J Am Coll Cardiol 1998;32:1648–56. [50] Keech A, Simes RJ, Barter P, et al. FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849–61. [51] King JM, Crouse JR, Terry JG, et al. Evaluation of effects of unmodified niacin on fasting and postprandial plasma lipids in normolipidemic men with hypoalphalipoproteinemia. Am J Med 1994;97:323–31.
[52] Grosskopf I, Ringel Y, Charach G, et al. Metformin enhances clearance of chylomicrons and chylomicron remnants in nondiabetic mildly overweight glucose-intolerant subjects. Diabetes Care 1997;20:1598–602. [53] van Wijk JPH, de Koning EJP, Castro Cabezas M, Rabelink TJ. Rosiglitazone improves postprandial triglyceride and free fatty acid metabolism in type 2 diabetes. Diabetes Care 2005;28:844–79. [54] Dormandy JA, Charobonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279–89. [55] Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457–71. [56] Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 2007;298:1189–95. [57] Ginsberg HN. Effects of statins on triglyceride metabolism. Am J Cardiol 1998;81(4A):32B–5B. [58] Castro Cabezas M, Verseyden C, Jansen H, Meijssen S. Effects of atorvastatin on the clearance of triglyceride rich lipoproteins in familial combined hyperlipidemia. J Clin Endocrinol Metab 2004;89:5972–80. [59] Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the curves study). Am J Cardiol 1998;81:582–7. [60] Pitt B, Waters D, Brown WV, et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med 1999;341:70–6. [61] Dupuis J, Tardif JC, Cernacek P, Theroux P. Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE (Reduction of Cholesterol in Ischemia and Function of the Endothelium) trial. Circulation 1999;99:3227–33.
Novel aspects of postprandial lipemia in relation to atherosclerosis A. Alipour, J.W.F. Elte, H.C.T. van Zaanen, A.P. Rietveld, M. Castro Cabezas ∗ Department of Internal Medicine, Sint Franciscus Gasthuis, Rotterdam, The Netherlands Received 30 January 2008; received in revised form 22 February 2008; accepted 13 May 2008
Abstract Postprandial hyperlipidemia is considered to be a substantial risk factor for atherosclerosis. Interestingly, this concept has never been supported by randomized clinical trials. The difficulty lies in the fact that most interventions aimed to reduce postprandial lipemia, will also affect LDL-C levels. The atherogenic mechanisms of postprandial lipids and lipoproteins can be divided into direct lipoprotein-mediated and indirect effects; the latter, in part, by inducing an inflammatory state. Elevations in postprandial triglycerides (TG) have been related to the increased expression of postprandial leukocyte activation markers, up-regulation of pro-inflammatory genes in endothelial cells and involvement of the complement system. This set of events is part of the postprandial inflammatory response, which is one of the recently identified potential pro-atherogenic mechanisms of postprandial lipemia. Especially, complement component 3 levels show a close correlation with postprandial lipemia and are also important determinants of the metabolic syndrome. In clinical practice, fasting TG are frequently used as reflections of postprandial lipemia due to the close correlation between the two. The use of serial capillary measurements in an out-ofhospital situation is an alternative for oral fat loading tests. Daylong TG profiles reflect postprandial lipemia and are increased in conditions like the metabolic syndrome, type 2 diabetes and atherosclerosis. Studies are needed to elucidate the role of postprandial inflammation in atherogenesis and to find new methods in order to reduce selectively the postprandial inflammatory response. Future studies are needed to find new methods in order to reduce selectively the postprandial inflammatory response. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Triglyceride-rich lipoproteins; Inflammation; Leukocytes; Complement
1. Introduction Disturbances of triglyceride (TG) metabolism are closely associated to atherosclerosis [1]. There is a close correlation between fasting and postprandial TG, although inter-individual differences may be high, in part due to differences in insulin sensitivity [2,3]. Subjects with fasting hypertriglyceridemia usually have elevated postprandial lipemia. Patients with obesity, diabetes mellitus and the metabolic syndrome have postprandial hyperlipidemia [4]. One of the proposed mechanisms has been competition Abbreviations: TRL, triglyceride-rich lipoproteins; CAD, coronary artery disease; C3, complement component 3; ASP, acylation stimulating protein; MBL, mannose-binding lectin. ∗ Corresponding author at: Department of Internal Medicine, Sint Franciscus Gasthuis, Center for Diabetes and Vascular Medicine, PO Box 10900, 3004 BA, Rotterdam, The Netherlands. Tel.: +31 10 4617267; fax: +31 10 4612692. E-mail address: [email protected] (M. Castro Cabezas). 1567-5688/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosissup.2008.05.007
between endogenous and exogenous TG-rich lipoproteins (TRLs) at different TG catabolic sites by overproduction of very low-density lipoproteins (VLDL) in the liver, in part due to hepatic insulin resistance. However, also patients with atherosclerosis with and without the metabolic syndrome, even in the presence of normal fasting TG, have postprandial hyperlipidemia [5,6]. Consequently, postprandial hyperlipidemia is a generalized phenomenon in high-risk conditions for atherosclerosis. Recently, inflammatory mechanisms have been associated with postprandial lipemia. These mechanisms include postprandial leukocyte activation, postprandial up-regulation of inflammation-associated genes in the endothelial cells and the activation of the complement system [7–10]. For example, complement component 3 (C3) is a strong determinant of postprandial lipemia and the metabolic syndrome [11], and it responds to treatment with statins [6]. In this paper we will review old and new concepts associated to postprandial lipemia and their role in atherogenesis.
40
A. Alipour et al. / Atherosclerosis Supplements 9 (2008) 39–44
2. Physiology of postprandial TG metabolism In the normal situation fasting TG are transported in the blood mainly in VLDL, containing apoB100 [12]. In the blood, VLDL is converted into VLDL remnants (IDL, intermediate density lipoproteins) by the action of lipoprotein lipase (LPL) attached to endothelial cells [13]. ApoCII present on the surface of VLDL (and chylomicrons) is a necessary co-factor for the hydrolysis of TG by LPL. ApoCIII, also a surface protein on VLDL (and chylomicrons), regulates the hydrolysis of TG by impeding the binding to LPL. In the circulation, VLDL remnants are enriched with apoE, the preferential ligand for the LDL-receptor and the hypothetical remnant receptor. Under physiological conditions IDL is taken up by LDL receptors in the liver where the lipoproteins are degraded and cholesterol is removed from the body by excretion into the bile. Part of IDL is degraded to LDL by the action of a different enzyme localized in the liver sinusoids, hepatic triglyceride lipase (HTGL). In the postprandial period, both VLDL and chylomicrons (with apoB100 and apoB48, respectively, as structural proteins) contribute to postprandial lipemia [12].
3. Epidemiological and observational evidence for the role of postprandial hyperlipidemia in atherosclerosis The concentration of fasting plasma TG is an independent risk factor for atherosclerosis, even in the range previously considered to be normal (below 2.0 mmol/L) [1]. Hypothetical mechanisms leading to atherosclerosis in hypertriglyceridemic subjects comprise exaggerated and prolonged postprandial lipemia with accumulation of atherogenic chylomicron remnants [5,14,15], the generation of small dense low density lipoproteins (LDL), decreased high density lipoprotein (HDL) concentrations and activation of leukocytes and endothelial cells by remnants and fatty acids [7–10]. All these mechanisms may be involved in the postprandial endothelial dysfunction as observed by several investigators [7–9,16], which is closely connected to atherosclerosis. Other processes contributing to endothelial dysfunctions are the generation of reactive oxidative species (ROS) and the formation of oxidized remnant lipoproteins [7,10]. These oxidized remnants are internalized by macrophages, eventually inducing foam cell formation [17]. In individual patient management, single fasting TG measurements are unreliable, with intra-individual coefficients of variation up to 60% [18]. In the Physicians Health Study, plasma TG levels 3–4 h after a meal distinguished better between cases with future myocardial infarction and controls than fasting plasma TG levels [19]. Recently, in a prospective study in healthy US women, it was shown that nonfasting TG levels, strongly and independently, predicted cardiovascular events even after adjustment for levels of total cholesterol and HDL-C and measures of insulin resistance [20]. In another large prospective study in Denmark, elevated
nonfasting TG levels were associated with increased risk of myocardial infarction, ischemic heart disease and death in men and women [21]. Several observational studies demonstrated delayed clearance of TRLs and suggested a direct relationship with the process of atherosclerosis in different groups [4–6,15,22,23].
4. Determinants of postprandial lipemia Many investigators have shown repeatedly that fasting TG is the major determinant of postprandial lipemia [2,3,5,15,23]. Other important parameters associated to postprandial lipemia are LPL and HTGL activities, HDL-C concentrations, apoB, apoE, apoCII and apoCIII. In addition, variables related to insulin sensitivity and the metabolic syndrome like the homeostatic model assessment (HOMA), waist circumference, fat mass and distribution are also closely correlated to the postprandial response [2–4,24]. Furthermore, high liver fat in subjects with nonalcoholic fatty liver disease has also been associated with an increased response of postprandial lipids in plasma, chylomicrons, and VLDL1 [25]. In contrast, the composition of the diet is only a weak determinant of the postprandial TG response [2,3,17,26]. Recently, associations between postprandial lipemia and other variables like the C3 and the acylation stimulating protein (ASP) have been reported. Activation of the complement system results in cleavage of C3, which is central in these pathways [27]. The C3/ASP-system has been recognized as a regulator of adipose tissue fatty acid metabolism [28]. ASP is identical to the desarginated form of the C3 split-product C3a (C3a-desArg), which is immunologically inactive. The C3/ASP pathway stimulates re-esterification of FFA into TG in adipocytes, reduces adipocyte FFA production by inhibiting hormone sensitive lipase and stimulates glucose uptake by adipocytes, fibroblasts and muscle cells [28]. C3 has been associated positively with fasting and postprandial TG, obesity, insulin resistance and the metabolic syndrome. Furthermore, C3 has been recognized as a strong predictor of myocardial infarction and complement activation also plays a role in the induction of tissue damage after myocardial infarction [29]. Macrophages may also activate C3 [30]. Recently, it has been shown that HDL3 from men with established coronary artery disease (CAD), is enriched with C3, suggesting that complement activation can occur by binding to HDL, which acts as an antigen [31] and that HDL may be the carrier of the C3 produced by macrophages in the sub-endothelium. Activation of the complement system leads to triggering of leukocytes, thereby promoting atherosclerosis (Fig. 1). Other factors involved in leukocyte activation are CRP, IL-6 and oxidative stress [29]. Another factor of the innate immune system, which recently has been associated to postprandial lipemia, is mannose-binding lectin (MBL) [32]. MBL is an important activating factor in the lectin pathway of the complement sys-
A. Alipour et al. / Atherosclerosis Supplements 9 (2008) 39–44
Fig. 1. Concept of the initiation of atherosclerosis in the bloodstream by the concerted action of leukocytes and the complement system. Triglyceriderich lipoproteins (TRLs) induce leukocyte activation. These leukocytes can activate the endothelium and induce the expression of cellular adhesion molecules (CAMs) and selectins, facilitating adherence of all leukocytes including lymphocytes. This will lead to adherence of these cells to the endothelium as well as the production of chemoattractants leading to the recruitment and activation of other leukocytes. The activated leukocytes are able to produce reactive oxygen species (ROS), which destabilize atherosclerotic lesions. Monocytes and lymphocytes transmigrate across the endothelial wall. Monocytes residing in the arterial wall differentiate into macrophages. Oxidative modification of LDL and remnants results in a highly atherogenic particle that can easily be taken up by macrophages. The latter can activate endothelial cells resulting in production of CAMs and pro-inflammatory cytokines (IL-6, IL-8 and MCP-1). Defects in the C3/ASP system (alternative pathway) lead to an enhanced flux of hepatic free fatty acids to the liver, which will in turn up-regulate hepatic VLDL secretion. The increase of lipoproteins in the bloodstream activates the classical pathway by CRP and binding of C3 to these lipoproteins (HDL3 ). Within the sub-endothelium the macrophages and foam cells also activate the classical pathway of the complement system. The activation of this pathway will promote leukocyte activation.
tem [27]. The reported frequency of MBL deficiency in the literature ranges from 11.1% to 41.5%. MBL deficiency has been associated to CAD and increased intimia media thickness (IMT) in carotid arteries [33,34]. Altogether, MBL may become an important determinant of atherosclerosis in the population.
41
Recent studies suggest alternative mechanisms. Postprandial TRLs of hyperlipidemic patients, and not of normotriglyceridemic subjects, modulate pro-inflammatory genes in endothelial cells and prolong the reduction of FMD beyond 8 h postprandially [8]. Postprandial and remnant lipoproteins may induce the expression of leukocyte adhesion molecules on the endothelium, facilitating recruitment of inflammatory cells. Activation of only endothelial cells is not sufficient to initiate the process of atherogenesis. Leukocyte activation and binding to the endothelium are obligatory steps [9,35]. A cytokine-controlled sequential up-regulation of selectins and adhesion molecules on activated leukocytes and endothelial cells is necessary. It has been shown that neutrophils increase postprandially with concomitant production of pro-inflammatory cytokines and oxidative stress and that these changes may contribute to endothelial dysfunction [7–10]. In healthy volunteers and in patients with premature atherosclerosis postprandial lipemia has been associated with the up-regulation of leukocyte activation markers [9,10]. Fasting leukocytes of patients with CVD have an increased lipid content when compared to controls and it was suggested that this was due to the uptake of chylomicrons in the bloodstream [36]. Recently, we have shown that apoB binds to neutrophils and monocytes and that postprandially, leukocytes become enriched with meal-derived fatty acids suggesting a direct interaction between lipoproteins and leukocytes by the leukocytes’ uptake of exogenous fatty acids in the bloodstream [37]. Increased residence time of atherogenic lipoproteins in plasma will result in enhanced binding of these particles to the endothelium thereby creating a marginated pool of endothelial bound lipoproteins [38], increasing the level of activation of the endothelial cells which potentially will expose more adhesion molecules on their surface [9,29]. These series of events will ultimately lead to the adhesion of inflammatory cells (especially, monocytes and lymphocytes but potentially also neutrophils) to the activated endothelium. Therefore, we have hypothesized that atherogenesis may start in the blood stream and not in the sub-endothelium as generally considered.
6. Methods to study postprandial lipemia 5. Novel atherogenic mechanisms of postprandial lipemia In the event that the liver is overproducing VLDL particles, like in (central) obesity, the metabolic syndrome, type 2 diabetes and familial combined hyperlipidemia (FCHL) [4,9,12,24], the common catabolic steps for VLDL and chylomicrons become saturated resulting in accumulation of both VLDL and chylomicron remnants. According to the classical concept of atherosclerosis by postprandial lipemia, remnant lipoproteins penetrate the vessel wall and are taken up by monocytes inducing foam cell formation. This may be one of the first steps in atherogenesis.
Several methods have been used to study chylomicron remnant metabolism. One should realize that these particles only represent part of postprandial response and that all lipoprotein factors are involved [12,13]. In line with the above description, both, the intestine and the liver secrete TRLs during the postprandial phase [12]. The methods to study the postprandial period depend on the area of interest. If TG metabolism is evaluated, simple oral fat loading tests may be used. Metabolic ward studies, however, may not provide a realistic impression of the free-living daytime situation and cannot be applied in clinical practice in large populations. Clinically applicable assays may be used to study
42
A. Alipour et al. / Atherosclerosis Supplements 9 (2008) 39–44
apoB48 levels and remnant particles [38]. However, these assays have not been proven to be reliable, cost-effective and time-effective yet [39]. An alternative could be the use of serial capillary measurements in an out-of-hospital situation [2–4,24,26]. Daylong TG profiles are closely related to postprandial lipemia as assessed by standardized oral fat loading tests and can be easily applied in clinical practice for routine screening of populations [3]. Repeated measurements of daylong triglyceridemia are less variable than fasting and postprandial capillary TG in normolipidemic subjects and in subjects with FCHL [18]. Daytime triglyceridemia has been associated with insulin resistance, body composition and diet [2–4,24,26]. Daytime TG profiles distinguish better between normolipidemic patients with CAD and healthy controls matched for age, gender and BMI than other lipid and non-lipid risk factors.
7. Strategies to reduce postprandial lipemia Without any doubt the first intervention should be lifestyle improvement. Weight reduction by lowering dietary energy intake and increased physical activity improves fasting and postprandial plasma lipids, insulin sensitivity, CRP, IL-6 and ASP levels [40]. Furthermore, weight decrease reduces also the progression of atherosclerosis determined by IMT [41]. Reduction of visceral adipose tissue has also been associated with improvement in apolipoprotein B-100 metabolism in obese men [42]. These findings are well in line with our observations that especially the waist circumference is related to diurnal triglyceridemia [2–4,24]. Treatment with fibrates is the first choice in hypertriglyceridemia improving both fasting and postprandial TGs [43]. Ciprofibrate therapy in type 2 diabetics has been shown to improve fasting and postprandial endothelial function, most likely by beneficial effects on TG and HDL metabolism [44]. In combined hyperlipidemia the use of gemfibrozil or fenofibrate decreased postprandial remnant-like particles [45]. It is so far unclear how these effects translate to primary end points in large clinical trials [46–50]. The use of fibrates reduces secondary events in patients with established coronary heart disease with low levels of HDL cholesterol [46,47] and a decrease of the progression of focal coronary atherosclerosis in young survivors of myocardial infarction [48,49]. However, fenofibrate did not reduce significantly the risk of coronary events in patients with type 2 diabetes in the fenofibrate intervention and event lowering in diabetes (FIELD) study [50]. An alternative for fibrates is niacin, which also decreases fasting and postprandial TG concentrations [51]. However, this is not a very popular drug because of its side effects. A different approach to reduce plasma TG concentrations may be improvement of insulin sensitivity by, for example, metformin or the thiazolidinedione derivatives (TZDs). In nondiabetic individuals who were mildly overweight and glucose intolerant, metformin therapy resulted in beneficial
effects in the clearance of postprandial lipoproteins [52]. It has been shown that rosiglitazone improves the metabolism of large TRLs and decreases postprandial FFA concentrations in type 2 diabetes [53]. However, the results of studies on the effects of TZDs on cardiovascular endpoints are inconclusive [54–56]. Although inhibitors of cholesterol synthesis (HMGCoA reductase inhibitors, statins) predominantly reduce LDL cholesterol levels, they also diminish plasma TG concentrations [6,10,12,38,57]. In several studies in humans and in animals, postprandial lipemia was also improved by the use of reductase inhibitors [12,38,58]. Moreover, the use of atorvastatin, with a pronounced effect on plasma TGs [59], during 18 months in patients with stable CAD was as effective as angioplasty and usual care [60]. These effects might be attributed, in part, to the pluripotential effects of statins besides reductions of plasma cholesterol and TG concentrations [61]. Furthermore, atorvastatin has been shown to decrease the postprandial marginated pool of atherogenic lipoproteins in subjects with FCHL [58]. This may represent an additive anti-atherogenic mechanism of treatment with statins that cannot be detected measuring only fasting plasma lipids. In addition, as described above, postprandial leukocyte activation may be an important target to reduce atherogenesis. Unfortunately, statin therapy does not reduce the postprandial increase of leukocyte activation markers in mildly hyperlipidemic patients with premature coronary sclerosis [10]. Future studies are needed to find new methods in order to reduce not only the postprandial lipemia, but also the postprandial inflammation.
8. Conclusions Overproduction of TRLs, characteristic for postprandial lipemia, leads to a complex series of events potentially inducing atherogenesis. These mechanisms can be divided into direct and indirect effects. Direct effects include increased residence time of atherogenic lipoproteins in plasma, resulting in enhanced binding of these particles to the endothelium thereby creating a marginated pool of endothelial cell-bound lipoproteins. The indirect pathway involves inflammatory aspects such as the activation of leukocytes and the endothelium, as well as the activation of the complement system. Inhibiting this pathway should be our next therapeutic goal.
Conflict of interest None.
References [1] Austin MA, Hokanson JE, Edwards KL. Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol 1998;81:7B–12B.
A. Alipour et al. / Atherosclerosis Supplements 9 (2008) 39–44 [2] Van Oostrom AJHHM, Castro Cabezas M, Ribalta J, et al. Diurnal triglyceride profiles in healthy normolipidemic male subjects are associated to insulin sensitivity, body composition and diet. Eur J Clin Invest 2000;30:964–71. [3] Castro Cabezas M, Halkes CJM, Meijssen S, van Oostrom AJHHM, Erkelens DW. Diurnal triglyceride profiles: a novel approach to study triglyceride changes. Atherosclerosis 2001;155:219– 28. [4] Van Wijk JPH, Halkes CJM, Erkelens DW, Castro Cabezas M. Fasting and daytime triglycerides in obesity with and without type 2 diabetes. Metabolism 2003;52:1043–9. [5] Groot PHE, van Stiphout WAHJ, Krauss XH, et al. Postprandial lipoprotein metabolism in normolipidemic men with and without coronary artery disease. Arterioscler Thromb 1991;11:653–62. [6] Halkes CJ, van Dijk H, de Jaegere PP, et al. Postprandial increase of complement component 3 in normolipidemic patients with coronary artery disease: effects of expanded-dose simvastatin. Arterioscler Thromb Vasc Biol 2001;21:1526–30. [7] Van Oostrom AJHHM, Sijmonsma TP, Verseyden C, et al. Postprandial recruitment of neutrophils may contribute to endothelial dysfunction. J Lipid Res 2003;44:576–83. [8] Norata GD, Grigore L, Raselli S, et al. Post-prandial endothelial dysfunction in hypertriglyceridemic subjects: molecular mechanisms and gene expression studies. Atherosclerosis 2007;193:321–7. [9] Alipour A, Elte JWF, Rietveld AP, van Zaanen HCT, Castro Cabezas M. Postprandial inflammation and endothelial dysfunction. Biochem Soc Trans 2007;35(Pt 3):466–9. [10] Van Oostrom AJHHM, Plokker HWM, van Asbeck BS, et al. Effects of rosuvastatin on postprandial leukocytes in mildly hyperlipidemic patients with premature coronary sclerosis. Atherosclerosis 2006;185:331–9. [11] Van Oostrom AJHHM, Alipour A, Plokker HWM, Sniderman AD, Castro Cabezas M. The metabolic syndrome in relation to complement component 3 and postprandial lipemia in patients from an outpatient lipid clinic and healthy volunteers. Atherosclerosis 2007;190:167– 73. [12] Castro Cabezas M, de Bruin TWA, Kock LAW, de Bruin TW. Postprandial apolipoprotein B100 and apo B48 in familial combined hyperlipidemia before and after reduction of fasting plasma triglycerides. Eur J Clin Invest 1994;24:669–78. [13] Karpe F, Tornvall P, Olivecrona T, et al. Composition of human low density lipoprotein: effects of postprandial triglyceride-rich lipoproteins, lipoprotein lipase, hepatic lipase and cholesteryl ester transfer protein. Atherosclerosis 1993;98:33–49. [14] Zilversmit DB. Atherogenesis: a postprandial phenomenon. Circulation 1979;60:473–85. [15] Karpe F, Steiner G, Uffelman K, Olivecrona T, Hamsten A. Postprandial lipoproteins and progression of coronary atherosclerosis. Atherosclerosis 1994;106:83–97. [16] Ceriello A, Taboga C, Tonutti L, et al. Evidence for an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial dysfunction and oxidative stress generation: effects of short-and long-term simvastatin treatment. Circulation 2002;106:1211–8. [17] Bravo E, Napolitano M. Mechanisms involved in chylomicron remnant lipid uptake by macrophages. Biochem Soc Trans 2007;35(Pt 3):459–63. [18] Delawi D, Meijssen S, Castro Cabezas M. Intra-individual variations of fasting plasma lipids, apolipoproteins and postprandial lipemia in familial combined hyperlipidemia compared to controls. Clin Chim Acta 2003;328:139–45. [19] Stampfer MJ, Krauss RM, Ma J, et al. A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. JAMA 1996;276:882–8. [20] Bansal S, Buring JE, Rifai N, et al. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA 2007;298:309–16.
43
[21] Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007;298:299–308. [22] Castro Cabezas M, de Bruin TW, Jansen H, et al. Impaired chylomicron remnant clearance in familial combined hyperlipidemia. Arterioscler Thromb 1993;13:804–14. [23] Patsch JR, Miesenb¨ock G, Patsch W. Relation of triglyceride metabolism and coronary disease. Studies in the postprandial state. Arterioscler Thromb 1992;12:1336–45. [24] Halkes CJM, Castro Cabezas M, van Wijk JPH, Erkelens DW. Gender differences in diurnal triglyceridemia in lean and overweight subjects. Int J Obes 2001;25:1767–74. [25] Matikainen N, M¨antt¨ari S, Westerbacka J, et al. Postprandial lipemia associates with liver fat content. J Clin Endocrinol Metab 2007;92:3052–9. [26] Van Wijk JPH, Castro Cabezas M, Halkes CJM, Erkelens DW. Effects of different nutrient intakes on daytime triacylglycerolemia in healthy, normolipemic, free-living men. Am J Clin Nutr 2001;74:171–8. [27] Walport MJ. Complement; first of two parts. N Engl J Med 2001;344:1058–65. [28] Cianflone K, Xia Z, Chen LY. Critical review of acylation-stimulating protein physiology in humans and rodents. Biochim Biophys Acta 2003;1609:127–43. [29] Van Oostrom AJ, van Wijk J, Castro Cabezas M. Lipaemia, inflammation and atherosclerosis: novel opportunities in the understanding and treatment of atherosclerosis. Drugs 2004;64(Suppl. 2):19–41. [30] Strunk RC, Kunke KS, Giclas PC. Human peripheral blood monocytederived macrophages produce haemolytically active C3 in vitro. Immunology 1983;49:169–74. [31] Vaisar T, Pennathur S, Green PS, et al. Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J Clin Invest 2007;117:746–56. [32] Alipour A, van Oostrom AJHHM, Van Wijk JPH, et al. Deficiency of mannose binding lectin is associated to impaired metabolism of VLDL1 particles despite fasting plasma triglycerides. Circulation 2007;Suppl.:1098. [33] Best LG, Davidson M, North KE, et al. Prospective analysis of mannose-binding lectin genotypes and coronary artery disease in American Indians. Circulation 2004;109:471–5. [34] Madsen HO, Videm V, Svejgaard A, Svennevig JL, Garred P. Association of mannose-binding lectin deficiency with severe atherosclerosis. Lancet 1998;352:959–60. [35] Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999;340:115–26. [36] Tertov VV, Kalenich OS, Orekhov AN. Lipid-laden white blood cells in the circulation of patients with coronary heart disease. Exp Mol Pathol 1992;57:22–8. [37] Alipour A, van Oostrom AJHHM, Izraeljan A, et al. Leukocyte activation by triglyceride-rich lipoproteins. Arterioscler Thromb Vasc Biol 2008;28:792–7 [Epub ahead of print]. [38] Verseyden C, Meijssen S, Castro Cabezas M. Effects of atorvastatin on fasting plasma and marginated apolipoproteins B48 and B100 in large, triglyceride-rich lipoproteins in familial combined hyperlipidemia. J Clin Endocrinol Metab 2004;89:5021–9. [39] Cohn JS. Postprandial lipemia and remnant lipoproteins. Clin Lab Med 2006;26:773–86. [40] Bruun JM, Verdich C, Toubro S, Astrup A, Richelsen B. Association between measures of insulin sensitivity and circulating levels of interleukin-8, interleukin-6 and tumor necrosis factor-alpha. Effect of weight loss in obese men. Eur J Endocrinol 2003;148:535–42. [41] Karason K, Wikstrand J, Sjostrom L, Wendelhag I. Weight loss and progression of early atherosclerosis in the carotid artery: a four-year controlled study of obese subjects. Int J Obes Relat Metab Disord 1999;23:948–56. [42] Riches FM, Watts GF, Hua J, et al. Reduction in visceral adipose tissue is associated with improvement in apolipoprotein B-100 metabolism in obese men. J Clin Endocrinol Metab 1999;84:2854–61.
44
A. Alipour et al. / Atherosclerosis Supplements 9 (2008) 39–44
[43] Fruchart JC, Brewer HB, Leitersdorf E. Consensus for the use of fibrates in the treatment of dyslipoproteinemia and coronary heart disease. Am J Cardiol 1998;81:912–7. [44] Evans M, Anderson RA, Graham J, et al. Ciprofibrate therapy improves endothelial function and reduces postprandial lipemia and oxidative stress in type 2 diabetes mellitus. Circulation 2000;101:1773–9. [45] Ooi TC, Cousins M, Ooi DS, Nakajima K, Edwards AL. Effect of fibrates on postprandial remnant-like particles in patients with combined hyperlipidemia. Atherosclerosis 2004;172:375–82. [46] Syv¨anne M, Nieminen MS, Frick H, et al. Associations between lipoproteins and the progression of coronary and vein-graft atherosclerosis in a controlled trial with gemfibrozil in men with low baseline levels of HDL cholesterol. Circulation 1998;98:1993–9. [47] Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of highdensity lipoprotein cholesterol. N Engl J Med 1999;341:410–8. [48] Ericsson CG, Hamsten A, Nilsson J, et al. Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients. Lancet 1996;347:849–53. [49] Ruotolo G, Ericsson C-G, Tettamanti C, et al. Treatment effect on serum lipoprotein lipids, apolipoproteins and low density lipoprotein particle size and relationships of lipoprotein variables to progression of coronary artery disease in the bezafibrate coronary atherosclerosis intervention trial (BECAIT). J Am Coll Cardiol 1998;32:1648–56. [50] Keech A, Simes RJ, Barter P, et al. FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849–61. [51] King JM, Crouse JR, Terry JG, et al. Evaluation of effects of unmodified niacin on fasting and postprandial plasma lipids in normolipidemic men with hypoalphalipoproteinemia. Am J Med 1994;97:323–31.
[52] Grosskopf I, Ringel Y, Charach G, et al. Metformin enhances clearance of chylomicrons and chylomicron remnants in nondiabetic mildly overweight glucose-intolerant subjects. Diabetes Care 1997;20:1598–602. [53] van Wijk JPH, de Koning EJP, Castro Cabezas M, Rabelink TJ. Rosiglitazone improves postprandial triglyceride and free fatty acid metabolism in type 2 diabetes. Diabetes Care 2005;28:844–79. [54] Dormandy JA, Charobonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279–89. [55] Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457–71. [56] Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 2007;298:1189–95. [57] Ginsberg HN. Effects of statins on triglyceride metabolism. Am J Cardiol 1998;81(4A):32B–5B. [58] Castro Cabezas M, Verseyden C, Jansen H, Meijssen S. Effects of atorvastatin on the clearance of triglyceride rich lipoproteins in familial combined hyperlipidemia. J Clin Endocrinol Metab 2004;89:5972–80. [59] Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the curves study). Am J Cardiol 1998;81:582–7. [60] Pitt B, Waters D, Brown WV, et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med 1999;341:70–6. [61] Dupuis J, Tardif JC, Cernacek P, Theroux P. Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE (Reduction of Cholesterol in Ischemia and Function of the Endothelium) trial. Circulation 1999;99:3227–33.