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Fish Oil Supplements During Perinatal Life
Chapter 24
Fish Oil Supplements During Perinatal Life: Impact on the Liver of Offspring Emilio Herrera, Encarnación Amusquivar Department of Biochemistry and Chemistry, University San Pablo CEU, Madrid, Spain
1. INTRODUCTION The fetus uses fatty acids as structural components, a source of energy, precursors of bioactive compounds, and regulators of transcription factors. Of the different fatty acids, the polyunsaturated fatty acids (PUFAs) play a key function in intrauterine and postnatal development. The essential fatty acids (EFAs), linoleic acid (LA, 18:2 n-6), and α-linolenic acid (ALA, 18:3 n-3), or their long-chain PUFA (LCPUFA) derivatives must be obtained from external sources, either from the diet or by supplementation. ALA and LA are the biosynthetic precursors (by elongation and desaturation) of the n-3 and n-6 LCPUFAs, respectively. In adults, none of the LCPUFAs are absolute dietary requirements, because they can be synthesized from the EFA precursors; in the fetus, term and preterm neonates, however, synthesis of LCPUFA from EFA is very limited and their plasma concentrations mainly depend on the maternal supply. It is well known that maternal concentrations of LCPUFAs during pregnancy correlate with those in the fetus and newborn. Furthermore, there is evidence to suggest that in humans, n-3 LCPUFAs have positive impacts on health such as the reduction of risk factors for several diseases, including nonalcoholic fatty liver disease (NAFLD). These considerations have been used to justify the advice that, during pregnancy and lactation, the maternal diet should contain an appropriate amount of fish or be supplemented with fish oil, which is rich in eicosapentaenoic acid (EPA, 20:5 n-3) and docosahexaenoic acid (DHA, 22:6 n-3). Moreover, fatty acids may alter the epigenome during the perinatal stage, with variable long-term metabolic and gene function consequences when adulthood is reached. This chapter reviews the role of fatty acids during perinatal development and the potential protective role of fish oil supplementation during the perinatal stages of NAFLD development.
2. ROLE OF FATTY ACIDS IN FETAL DEVELOPMENT From the onset of gestation, the human embryo and the fetus require PUFA for their normal development. Until approximately 25 weeks of gestation, fetal accumulation of specific fatty acids is relatively small, but increases logarithmically with gestational age to reach its maximal accretion rate during the last 5 weeks of intrauterine life.1,2 It has been estimated in Western populations, in the late weeks of pregnancy, that the PUFA with the highest rate of whole body fetal accretion is LA followed by two LCPUFAs, arachidonic acid (AA, 20:4 n-6) and DHA.3 At term and throughout the first 2 years of life, DHA is the fatty acid present in the highest proportion in the phospholipids of neuronal membranes of the cerebral cortex and in the retinal photoreceptors.4 During pregnancy and the neonatal period, in the fetus and newborn, both retinal function and learning ability become permanently impaired if the accumulation of DHA is insufficient,5 and low levels of DHA in premature infants have been shown to affect their eye and brain functions.6,7 Visual acuity has been shown to improve in preterm infants fed formula containing a DHA supplement.8 These and other related findings have motivated dietary supplementation with fish oil, which is rich in DHA and its metabolic precursor, EPA, in pregnant women, although the findings are not yet conclusive (see below). Fatty acid oxidation also seems to play a major role in fetal development. The fetus has traditionally been considered to be dependent on glucose oxidation for energy production. However, several recessively inherited disorders in genes of the mitochondrial fatty acid oxidation (MFAO) system have been associated with prematurity, intrauterine growth retardation, and hepatic encephalopathy.9 Furthermore, it has been shown in several tissues of the human fetus that there is substantial mRNA expression and activity of MFAO enzymes.10 These findings have led to the proposal that fatty acid oxidation plays Dietary Interventions in Liver Disease. https://doi.org/10.1016/B978-0-12-814466-4.00024-0 Copyright © 2019 Elsevier Inc. All rights reserved.
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an important role in the human fetus, contributing greatly to its development.11 In animal studies, disturbances of the MFAO pathway have also been shown to lead to fetal demise and fetal growth retardation, and to reduce fertility.12 It may therefore be concluded that fatty acids play a key role in fetal development, their oxidation playing an important role as a source of energy also being essential. This is particularly so in case of the LCPUFAs, which are precursors of bioactive compounds and are involved in the structure and function of the nervous system and retina.2 Although the fetus is able to synthesize saturated and monounsaturated fatty acids,13 the LCPUFAs are of maternal origin; they are the main fatty acids crossing the placenta1 and are probably the preferred oxidative substrate for the fetus, being essential therefore in its development.2
3. FATTY ACIDS AND EPIGENETICS Epigenetics can be defined as a hereditable DNA activity that depends on its chemical modifications and adjacent regulatory proteins that are independent of the DNA sequence.14,15 Epigenetic markers include the addition to DNA of a methyl group, which is covalently attached to a cytosine of a CpG dinucleotide. The degree of DNA methylation within the genome is cell and tissue specific and is usually associated with decreased gene expression. On the other hand, hypomethylation is associated with increased gene expression.16 Another epigenetic marker is the modification of histones which, as well as packaging DNA, play a significant role in posttranslational modifications of amino acids, such as acetylation, methylation, or phosphorylation.17 An additional epigenetic marker is the activity of noncoding RNAs such as microRNAs, interference RNAs, long-chain RNAs, and antisense RNAs.18,19 These noncoding RNAs regulate several cellular processes by posttranscriptionally regulating gene expression through their pairing to the messenger RNA.20 Because of the influence of maternal metabolism on embryo development during pregnancy and the plasticity of epigenetic regulation during development, the impact of nutrition during early life has been linked to health and diseases in later life.21 There is now emerging evidence that dietary fatty acids and fats during the perinatal period can alter the epigenome, and it is well established that modifying the amount and quality of fatty acids, especially the n-3 PUFA, in the maternal diet may affect the epigenetic outcomes in the offspring.22 The n-3 PUFAs have been shown to have antilipidemic effects through the promotion of lipolysis and fatty acid oxidation and the inhibition of lipogenesis and circulating triacylglycerol (TAG) concentrations, as well as antiatherogenic, antiinflammatory, and anti-cell-development properties in humans. Although prospective observational studies have shown inconsistent associations between dietary or circulating n-3 LCPUFAs and the risk of coronary heart disease or the risk of all-cause mortality, metaanalysis of randomized controlled trials involving a sufficient number of participants has suggested that they are inversely associated with both coronary heart disease23 and all-cause mortality.24 These effects are brought about by the ability of n-3 LCPUFAs to regulate the expression of different genes, by changing the methylation at the cytosine in the CpG islands of DNA25,26 or by modulating the expression of some noncoding RNAs,27 thereby modifying the epigenome. In this regard, it has been shown that certain fatty acids could modulate the expression of miRNA in different cell types in vitro.28–30 The evidence for these effects in vivo is limited;31,32 but we fed pregnant rats with isoenergetic diets which contained 9% oils with different fatty acid compositions from conception to day 12 of pregnancy, after which they were fed with a standard diet until the end of the study. In the liver of a 12-month-old male offspring, the expression of miRNAs such as miR-215, miR-10b, miR-377-3p, and miR-192, among others, was found to be differentially modulated by the different fatty acids consumed by the dams during just the first half of pregnancy.33 A decrease in the expression of hepatic miRNAs and an increase in the expression of target genes related to insulin signaling were found in the offspring from dams given the fish oil supplemented diet during just the first half of pregnancy when compared with those given either soybean-, olive-, linseed- or palm-oil supplements.33 These findings clearly fit with both the reduced fat accretion and the age-related decline in insulin sensitivity found in 12-month-old male offspring of rats given the fish oil diet during early pregnancy.34 Such an effect was not, however, found in female offspring, which agrees with the reported significant differences in the way human males and females metabolize and store n-3 PUFAs26,35 as well as the gender-dependent global genomic DNA methylation36 and infant epigenome after prenatal DHA supplementation.37 The precise mechanism(s) underlying the epigenetic effects induced by a particular type of fatty acid is not completely elucidated. Nevertheless, this area of research—into how dietary fatty acids can modify the epigenome—is both valid and important because it will provide new insights into the effects of dietary fatty acids on development, metabolism and risk of disease, and the mechanisms thereof.
4. FISH OIL SUPPLEMENTS DURING PREGNANCY Although it is known that, at the time of birth, human newborns can synthesize both AA and DHA from their respective EFA, LA or ALA, respectively, the process is limited.38,39 Therefore, because those LCPUFA are a requirement for appropriate fetal development during the intrauterine life, they must come from maternal circulation by placental transfer.2
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Despite the molecular mechanism of this process not being completely understood,40 it is known to occur at a high rate.41 Whereas the proportion of both AA and DHA in human maternal circulation declines during late pregnancy, their percentage in the neonate at birth is higher than that in the mother.42 It has been shown in both humans43 and rats13 that plasma concentrations of LCPUFAs in maternal circulation correlate with those in the fetus. On the basis of these and other similar findings, the current advice is that maternal diet should be supplemented with fish oil during the last months of pregnancy. However, under these circumstances, low levels of AA are frequently found in the mother and the fetus, both in humans44,45 and rats.46,47 This is probably a consequence of the known effects of the two main LCPUFAs present in fish oil, DHA and EPA, inhibiting Δ5- and Δ6-desaturases, which are rate-limiting enzymes for AA synthesis from its essential precursor, LA. This is of particular importance for intrauterine growth and development because plasma concentrations of AA have been correlated to body weight in preterm infants and early human growth, and therefore an adverse effect of fish oil supplementation related to low plasma AA has been proposed.48,49 Although in many countries fish oil is currently the most common dietary supplement during pregnancy, with the exception of vitamins and minerals, the evidence for the benefits to the mother or the offspring is not yet well established. Indeed, randomized controlled trials have produced contradictory results.50 There have been many clinical trials designed to determine the potential benefits of fish oil supplementation during pregnancy, but the evidence is still weak. Fish oil supplements during pregnancy have been shown not to prevent preterm birth problems (including reductions in the number of offspring in rats) or to bring about improvements in neonatal outcome.51 It has been reported that they do not prevent preeclampsia or intrauterine growth restriction50 or reduce the risk of gestational diabetes and related pathologies.52 Even in rats it has been shown that excessive consumption of fish oil during pregnancy and lactation causes adverse effects on newborn body weight and neurological development.46 In humans, it has been shown that oxidative stress during pregnancy is associated to adverse effects to the mother and the offspring.53,54 The large number of double bonds in LCPUFA make it prone to oxidation, producing a variety of lipid peroxides, and therefore the intake of oxidized fish oil may increase lipid peroxidation and reduce antioxidant capacity. It has been proposed that the variable response to fish oil supplements during the periuterine phase could be related to its degree of oxidation because commercial preparations have been shown to exceed the recommended levels of oxidation markers as well as not meeting the content of n-3 LCPUFA claimed on the label.55 Studies in humans56,57 and in experimental animals58 have shown that prenatal and early postnatal dietary fatty acids, particularly PUFA, may affect the development of the fetus and newborn to have programming effects in the future by altering the development of diseases such as obesity, diabetes, cancer, cardiovascular diseases, or liver disorders in adults. The knowledge of programming effects from fish oil intake during pregnancy, lactation, or both in humans is limited. It has been shown in children that increased n-3 LCPUFA status during pregnancy causes lower adiposity59 and that the intake of cod liver oil during pregnancy reduces the risk of type 1 diabetes.60 There are also reports where daily supplementation with fish oil during the last trimester of pregnancy was not associated with either adiposity or insulin sensitivity values in 19-year-old offspring.61 The studies on long-term effects of fish oil intake during the perinatal stage in experimental animals are also scarce and variable, results showing that the dose and time window of supplementation is of importance.62–64 In offspring of rats fed with a diet containing 10% fish oil, compared with those fed the same diet but containing 10% olive oil, we have found that whereas at 2 months of age insulin sensitivity was increased, at 4 months no differences were found, but at 18 months a decreased insulin sensitivity was found in the fish oil group.65 However, by feeding rats with isocaloric diets containing 9% of fat based on soybean, olive, fish, linseed, or palm oil during just the first 12 days of pregnancy (roughly first half of pregnancy) and standard laboratory diet onward, we found that male pups at 12 months of age of those from the fish oil group have decreased lumbar adipose tissue weight and an increased insulin sensitivity index compared with those of the other groups. These same variables did not differ, however, between the groups in 12-month-old female offspring.34 These findings differ from those of Siemelink et al.66 in offspring of dams given a diet containing 18% fish oil from 2 weeks prior pregnancy and until the end of lactation, showing no effect on insulin sensitivity at 12 weeks of age, which again points out the importance of dose and time window of the fish oil supplement during pregnancy. From studies in rats, it seems that a moderate amount of fish oil intake during the first half of pregnancy rather than high doses are needed to reduce insulin resistance and adipose tissue mass in the adult male offspring but not in females.34 Because the potential change in the DNA marker in the embryo caused by maternal fish oil intake occurred during early pregnancy before sex differentiation of the gonads, it appears that differential hormonal environment in adult males versus females is responsible for the different gender responses of adult insulin sensitivity to the maternal fish oil diet intake. The mechanism underlying these effects is epigenetic and could be explained in part by the influence on miRNA expression33 as stated above.
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5. PREVALENCE AND PATHOGENIC ASPECTS OF NONALCOHOLIC FATTY LIVER DISEASE NAFLD is rapidly becoming the most common cause of chronic liver disease in the Western world.67 It represents a wide spectrum of diseases, including hepatocellular steatosis, steatohepatitis, and cirrhosis and is characterized by an abnormal accumulation of fat in the liver in patients with mild or absent alcohol ingestion.68 It has an increasing importance because of its high prevalence, which is estimated to be around 25% of the adult population in the world.69 It is also known that NAFLD is the most common form of liver disease in children and adolescents,70 its prevalence having more than doubled in the last two decades71 and has increased 10-fold since 1975.72 NAFLD patients are generally asymptomatic with mild, fluctuating elevations in liver enzymes but can progress to nonalcoholic steatohepatitis (NASH), fibrosis, and ultimately cirrhosis, which may progress to hepatocellular carcinoma.73 NAFLD is an umbrella term for a range of liver conditions ranging from simple steatosis at the lower end to NASH at the most severe end. In fact, some patients with simple steatosis progress to NASH, and according to the “two-hit” theory, proposed by Day and James in 1998,74 liver steatosis sensitizes hepatocytes to the second hit. This second insult may be caused by increased oxidative stress capable of initiating lipid peroxidation, mitochondrial dysfunction, cytokine or adipokine imbalance, lipotoxicity of nonesterified fatty acids (NEFAs), hepatic accumulation of cholesterol, and the activation of innate immunity.75 The main difference between simple steatosis and NASH is the degree of hepatocyte injury and apoptosis. Increased apoptosis is thought by some authors to be the third hit involved in NAFLD pathogenesis.76 Like adults, children with NAFLD can progress to cirrhosis and end-stage liver disease.77 The pathogenesis of NAFLD in humans is very complex and not yet fully understood, having a variety of risk factors such as nutritional habits, physical inactivity, chronic stress, and lifestyle, apart from genetic susceptibility. There is a great association between obesity, metabolic syndrome, insulin resistance, type 2 diabetes, and NAFLD,68,78 and the increases in the prevalence of all of them are strongly linked to changes in dietary habits. An accumulation of TAGs in liver is a characteristic of NAFLD. These TAGs are formed in hepatocytes by the esterification of the active forms of fatty acids (acyl-CoA) and glycerol (glycerol-3-phosphate). Fatty acids in liver arise from three sources: (1) endogenous lipogenesis de novo, (2) diet, and (3) adipose tissue lipolysis, which corresponds to the hydrolysis of accumulated TAGs to NEFAs and glycerol, and the release of NEFA into blood to reach the liver. In the liver, fatty acids may be broken down by β-oxidation or reesterified to form TAGs again that may be subsequently stored as lipid droplets or be exported into the circulation in the form of very low–density lipoproteins (VLDL). These lipoproteins are formed in the liver by the incorporation of TAG into apolipoprotein B–containing structures by the action of the microsomal TAG transfer protein (MTP). Hepatic TAG accumulation can therefore result from the imbalance of increased NEFA arrival and subsequent reesterification, increased lipogenesis, decreased fatty acid oxidation, decreased VLDL export, or a combination of these events. A reduction of MTP activity or apo B synthesis and VLDL secretion impairs hepatic TAG export and favors their hepatic accumulation.79,80
6. FETAL PROGRAMMING ORIGINS OF NAFLD The first report of an altered intrauterine environment resulting in low-birth-weight newborns associated with the risk of a number of diseases including obesity, diabetes, and cardiovascular risk in adulthood was by Barker and coworkers81–83 and was later extended to large-for-gestational-age babies.84 The concept of fetal programming refers to the conditions in utero or the insults during intrauterine life, such as the nutrients the fetus receives during gestation, that play an important role in health during the whole life of an individual. There is now evidence that fetal metabolic programming caused by the intrauterine nutritional environment is influenced by epigenetic changes that involve changes in gene expression caused by chromatin remodeling, such as methylation of DNA and histone modifications, as described above for fatty acids.85 The increased prevalence of maternal obesity and gestational diabetes mellitus during the last half century86,87 are thought to have increased the risk of juvenile obesity and other metabolic diseases, including NAFLD in the offspring,77 which as stated above is the most common chronic human liver disease. The mechanism(s) whereby excess maternal nutrition affects fetal development is still poorly understood, but it has been proposed that immature—and even lack of—adipose tissue in most species until relatively late in pregnancy may be responsible for the fetus being vulnerable to steatosis. This includes humans, where the fetal adipose tissue deposition occurs primarily over the final third of gestation88 and may not be sufficient to act as a buffer for excessive transplacental delivery of lipid, as can be the case when the mother is obese or hyperlipidemic. Several experimental studies carried out in rodents89–91 and in nonhuman primates (NHP)92 have shown that maternal obesogenic diets with a high-fat content can program hepatic steatosis (NAFLD) or even NASH in the offspring. Also, an excess of sucrose or fructose consumption during pregnancy, which is associated with the development of type 2 diabetes, obesity, and hyperlipidemia, has been shown in rodents to cause a fatty liver in the offspring.93,94 Moreover, when diets
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containing high fat and high sugar, like the so-called cafeteria or junk food diets, are applied during pregnancy, young offspring have consistently shown signs of NAFLD,95–97 and these signs were exacerbated when the offspring were exposed to junk food during pregnancy, lactation, and after weaning, showing hepatic steatosis, hepatic ballooning, oxidative stress, and altered expression of genes involved in glucose and lipid metabolism.98 In pregnant NHP the fetal liver of those chronically fed a high-fat diet (HFD) have been shown to have increased TAG concentrations and evidence of oxidative stress that are consistent with the development of NAFLD.92 Not all the NHP given the HFD developed obesity and insulin resistance, but all fetal offspring of HFD mothers showed all the signs of early NAFLD at the third trimester of intrauterine life, and the increased liver TAG concentration persisted until at least 180 days postnatally. The mechanisms by which maternal obesity or the ingestion of high-calorie processed food during the perinatal stages can lead to NAFLD development in the fetus and later offspring are not completely known. It may be driven in part by an increased delivery of maternal nutrients to the fetus, especially lipids. Under those conditions, maternal hyperlipidemia becomes exaggerated. Fatty acids cross the placenta with difficulties, in spite of several intrinsic factors within the placenta, but their quantitative maternal–fetal transfer is mainly driven by the gradient.40 In studies in normal healthy women designed to determine the contribution of nutrients in maternal circulation to fetal metabolic variables, we showed that maternal glucose, NEFA, and glycerol, but not TAG, correlate positively and linearly with those in cord blood.99 As reviewed recently,100 under these healthy conditions, maternal glucose reaching the fetus as a result of its maternal/fetal gradient is used by fetal liver partially to synthesize fatty acid (i.e., de novo lipogenesis) and for subsequent esterification of acyl-CoA with glycerol-3-phosphate for the synthesis of TAG. Maternal oral glucose load in rats has been shown to increase fetal liver lipogenesis,101 and in mice maternal fat intake has been shown to upregulate the hepatic expression of genes involved in hepatic TAG synthesis.89 Taking into account the above-mentioned maternal–fetal metabolic interactions, we propose the picture shown in Fig. 24.1 to interpret the fetal induction of NAFLD under conditions of enhanced maternal/ fetal glucose gradient and maternal hyperlipidemia, as it is often the case of maternal obesity or diabetic conditions. The TAGs synthesized in fetal liver from maternal glucose crossing the placenta are pooled with those also formed in fetal liver from the plasma NEFA that are derived from placental transfer of fatty acids. Those latter fatty acids are carried in maternal circulation associated to lipoproteins in their esterified form102 and are hydrolyzed in the placenta by the action of placental lipases (endothelial lipase, lipoprotein lipase, and phospholipase A2) and released as NEFA to fetal circulation. During late gestation, fetal liver TAGs are released into the circulation in the form of TAG-rich lipoproteins that are hydrolyzed by adipose tissue lipoprotein lipase, thus facilitating the uptake and intracellular reesterification of the lipolytic products to form TAG for their accumulation in adipose tissue. Over this picture, there are at least two aspects that should be taken into account to understand the increase of liver TAG under conditions of exaggerated maternal hyperlipidemia: (1) The excess of TAG liver accumulation is mainly the result of increased liver uptake of circulating NEFA derived from maternal lipid transfer and (2) in humans, fetal adipogenesis takes place from around the 14th week of gestation,103 but fetal fat accretion does not accelerate until the last weeks of gestation.104 It has been hypothesized that, under conditions of excess nutrition such as maternal high-fat diet, obesity, and gestational diabetes mellitus, especially during early pregnancy, the fetus utilizes the liver for energy storage.77,92 Therefore, increased placental transfer of maternal fuels such as glucose and fatty acids is responsible for increased hepatic TAG storage in the fetus, especially when sufficient adipose tissue is not available as a storage buffer to handle excess nutrition.
7. POTENTIAL PROTECTIVE ROLE OF FISH OIL IN THE NAFLD DEVELOPMENT As well as the changes reported above, it is known that an excess of dietary lipids during pregnancy may impact several pathways in fatty acid metabolism that could contribute to their fetal metabolic programming effect. In fact, it is known that development of NAFLD in rats is associated with an increase in the expression of genes that take part in lipogenesis (i.e., acetyl CoA carboxylase [ACC], fatty acid synthase [FAS], and stearoyl-CoA desaturase-1 [SCD1]) or regulate this pathway (i.e., sterol regulatory element-binding protein 1c [SREBP-1c] and liver X receptor-α [LXR α])105 as well as decrease the expression of genes associated with hepatic fatty acid oxidation such as peroxisome proliferator–activated receptor α (PPAR-α), carnitine palmitoyl transferase-1 (CPT-1), and mitochondrial matrix proteins.106 The n-3 LCPUFAs present in fish oil (EPA and DHA) have major functions in the regulation of hepatic lipid metabolism.107 They decrease de novo lipogenesis by inhibiting the expression of the transcription factor SREBP-1c as well as the transcription of lipogenic genes. They also increase liver uptake of NEFA and fatty acid oxidation through the activation of both PPARγ108 and PPARα109,110 as well as downregulating the expression of proinflammatory genes.111 These effects of fish oil have been considered together with other actions to be a viable therapeutic strategy for NAFLD. In fact, there are studies showing that fish oil supplementation to mice already consuming an HFD, and consequently developing liver steatosis, results in reduced hepatic lipid content, increased antioxidant responses, increased insulin sensitivity, favored
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FIGURE 24.1 Schematic picture of the proposed mechanism by which maternal obesity or hyperlipidemic and hyperglycemic conditions can lead to the development of nonalcoholic fatty liver disease in the fetus. Details are reported in the text. EL, endothelial lipase; LPL, lipoprotein lipase; NEFA, nonesterified fatty acids; PL-A2, phospholipase A2; TAG, triacylglycerols.
fatty acid oxidation as a result of PPARα activation, downregulation of expression of SREBP-1c, and antiinflammatory effects.112,113 Furthermore, a literature search of preclinical and clinical studies has shown an ameliorative effect of dietary supplements of fish oil or purified n-3 LCPUFAs in NAFLD, by reducing hepatic lipid content, arriving at the conclusion that they appear safely to reduce nutritional fatty liver disease in adults.114 In spite of these positive results, some harmful effects of high maternal doses of fish oil or DHA supplements in women have also been reported,115 and recent reviews of the scientific literature have concluded that the association of maternal fish or fish oil consumption during pregnancy with child health outcomes has been largely inconsistent.42,50,116 Therefore, additional studies using different doses of fish oil supplements or natural sources of n-3 LCPUFAs and at different time intervals during perinatal life to determine their long-term health benefits in the offspring are warranted.
ACKNOWLEDGMENTS The authors thank Dr. Peter Dodds for editing and linguistic revision of the manuscript. Preparation of this chapter was carried out in part with grants from the Universidad San Pablo-CEU and the Fundación Ramón Areces (CIVP16A1835) of Spain.
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PLoS One 2013;8:e69817. 28. Davidson LA, Wang N, Shah MS, Lupton JR, Ivanov I, Chapkin RS. n-3 Polyunsaturated fatty acids modulate carcinogen-directed non-coding microRNA signatures in rat colon. Carcinogenesis 2009;30:2077–84. 29. Zhu L, Shi C, Ji C, Xu G, Chen L, Yang L, Fu Z, Cui X, Lu Y, Guo X. FFAs and adipokine-mediated regulation of hsa-miR-143 expression in human adipocytes. Mol Biol Rep 2013;40:5669–75. 30. Gil-Zamorano J, Martin R, Daimiel L, Richardson K, Giordano E, Nicod N, Garcia-Carrasco B, Soares SM, Iglesias-Gutierrez E, Lasuncion MA, Sala-Vila A, Ros E, Ordovas JM, Visioli F, Davalos A. Docosahexaenoic acid modulates the enterocyte Caco-2 cell expression of microRNAs involved in lipid metabolism. J Nutr 2014;144:575–85. 31. Benatti RO, Melo AM, Borges FO, Ignacio-Souza LM, Simino LA, Milanski M, Velloso LA, Torsoni MA, Torsoni AS. Maternal high-fat diet consumption modulates hepatic lipid metabolism and microRNA-122 (miR-122) and microRNA-370 (miR-370) expression in offspring. Br J Nutr 2014;111:2112–22. 32. Parra P, Serra F, Palou A. Expression of adipose microRNAs is sensitive to dietary conjugated linoleic acid treatment in mice. PLoS One 2010;5:e13005. 33. Casas-Agustench P, Fernandes FS, Tavares do Carmo MG, Visioli F, Herrera E, Davalos A. Consumption of distinct dietary lipids during early pregnancy differentially modulates the expression of microRNAs in mothers and offspring. PLoS One 2015;10:e0117858. 34. Sardinha FL, Fernandes FS, Tavares do Carmo MG, Herrera E. Sex-dependent nutritional programming: fish oil intake during early pregnancy in rats reduces age-dependent insulin resistance in male, but not female, offspring. Am J Physiol Regul Integr Comp Physiol 2013;304:R313–20. 35. Lohner S, Fekete K, Marosvolgyi T, Decsi T. Gender differences in the long-chain polyunsaturated fatty acid status: systematic review of 51 publications. Ann Nutr Metab 2013;62:98–112. 36. Zhang FF, Cardarelli R, Carroll J, Fulda KG, Kaur M, Gonzalez K, Vishwanatha JK, Santella RM, Morabia A. Significant differences in global genomic DNA methylation by gender and race/ethnicity in peripheral blood. Epigenetics 2011;6:623–9. 37. van Dijk SJ, Zhou J, Peters TJ, Buckley M, Sutcliffe B, Oytam Y, Gibson RA, McPhee A, Yelland LN, Makrides M, Molloy PL, Muhlhausler BS. Effect of prenatal DHA supplementation on the infant epigenome: results from a randomized controlled trial. Clin Epigenet 2016;8:114. 38. Carnielli VP, Simonato M, Verlato G, Luijendijk I, De Curtis M, Sauer PJ, Cogo PE. Synthesis of long-chain polyunsaturated fatty acids in preterm newborns fed formula with long-chain polyunsaturated fatty acids. Am J Clin Nutr 2007;86:1323–30. 39. Carlson SE, Colombo J. Docosahexaenoic acid and arachidonic acid nutrition in early development. Adv Pediatr 2016;63:453–71. 40. Herrera E, Lasunción MA. Maternal-fetal transfer of lipid metabolites. In: Polin RA, Abman SH, Rowitch DH, Beinits WE, Fox WW, editors. Fetal and neonatal physiology, vol. 1. Philadelphia (PA): Elsevier; 2017. p. 342–53. 41. Lewis RM, Desoye G. Placental lipid and fatty acid transfer in maternal overnutrition. Ann Nutr Metab 2017;70:228–31. 42. Herrera E, Casas-Agustench P, Dávalos A. Maternal fish oil intake and insulin sensitivity in the offspring. In: Rajendram R, Preedy VR, Patel VB, editors. Diet, nutrition and fetal programming. Springer; 2017. p. 261–77.
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43. Matorras R, Perteagudo L, Sanjurjo P, Ruiz JI. Intake of long chain w3-polyunsaturated fatty acids during pregnancy and the influence of levels in the mother on newborn levels. Eur J Obstet Gynecol Reprod Biol 1999;83:179–84. 44. Helland IB, Smith L, Saarem K, Saugstad OD, Drevon CA. Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy and lactation augments children’s IQ at 4 years of age. Pediatrics 2003;111:e39–44. 45. van Goor SA, Dijck-Brouwer DA, Erwich JJ, Schaafsma A, Hadders-Algra M. The influence of supplemental docosahexaenoic and arachidonic acids during pregnancy and lactation on neurodevelopment at eighteen months. Prostaglandins Leukot Essent Fatty Acids 2011;84:139–46. 46. Amusquivar E, Ruperez FJ, Barbas C, Herrera E. Low arachidonic acid rather than alpha-tocopherol is responsible for the delayed postnatal development in offspring of rats fed fish oil instead of olive oil during pregnancy and lactation. J Nutr 2000;130:2855–65. 47. Jimenez MJ, Bocos C, Panadero M, Herrera E. Fish oil diet in pregnancy and lactation reduces pup weight and modifies newborn hepatic metabolic adaptations in rats. Eur J Nutr 2017;56:409–20. 48. Carlson SE, Werkman SH, Peeples JM, Cooke RJ, Tolley EA. Arachidonic acid status correlates with first year growth in preterm infants. Proc Natl Acad Sci USA 1993;90:1073–7. 49. Koletzko B, Braun M. Arachidonic acid and early human growth: is there a relation? Ann Nutr Metab 1991;35:128–31. 50. Saccone G, Saccone I, Berghella V. Omega-3 long-chain polyunsaturated fatty acids and fish oil supplementation during pregnancy: which evidence? J Matern Fetal Neonatal Med 2016;29:2389–97. 51. Saccone G, Berghella V. Omega-3 long chain polyunsaturated fatty acids to prevent preterm birth: a systematic review and meta-analysis. Obstet Gynecol 2015;125:663–72. 52. Chen B, Ji X, Zhang L, Hou Z, Li C, Tong Y. Fish oil supplementation does not reduce risks of gestational diabetes mellitus, pregnancy-induced hypertension, or pre-eclampsia: a meta-analysis of randomized controlled trials. Med Sci Monit 2015;21:2322–30. 53. Gitto E, Reiter RJ, Karbownik M, Tan DX, Gitto P, Barberi S, Barberi I. Causes of oxidative stress in the pre- and perinatal period. Biol Neonate 2002;81:146–57. 54. Little RE, Gladen BC. Levels of lipid peroxides in uncomplicated pregnancy: a review of the literature. Reprod Toxicol 1999;13:347–52. 55. Albert BB, Derraik JG, Cameron-Smith D, Hofman PL, Tumanov S, Villas-Boas SG, Garg ML, Cutfield WS. Fish oil supplements in New Zealand are highly oxidised and do not meet label content of n-3 PUFA. Sci Rep 2015;5:7928. 56. Lucas A. Programming by early nutrition in man. Ciba Found Symp 1991;156:38–50. Discussion 50–35. 57. Mennitti LV, Oliveira JL, Morais CA, Estadella D, Oyama LM, Oller do Nascimento CM, Pisani LP. Type of fatty acids in maternal diets during pregnancy and/or lactation and metabolic consequences of the offspring. J Nutr Biochem 2015;26:99–111. 58. Zambrano E, Bautista CJ, Deas M, Martinez-Samayoa PM, Gonzalez-Zamorano M, Ledesma H, Morales J, Larrea F, Nathanielsz PW. A low maternal protein diet during pregnancy and lactation has sex- and window of exposure-specific effects on offspring growth and food intake, glucose metabolism and serum leptin in the rat. J Physiol 2006;571:221–30. 59. Donahue SM, Rifas-Shiman SL, Gold DR, Jouni ZE, Gillman MW, Oken E. Prenatal fatty acid status and child adiposity at age 3 y: results from a US pregnancy cohort. Am J Clin Nutr 2011;93:780–8. 60. Stene LC, Ulriksen J, Magnus P, Joner G. Use of cod liver oil during pregnancy associated with lower risk of Type I diabetes in the offspring. Diabetologia 2000;43:1093–8. 61. Rytter D, Bech BH, Christensen JH, Schmidt EB, Henriksen TB, Olsen SF. Intake of fish oil during pregnancy and adiposity in 19-y-old offspring: follow-up on a randomized controlled trial. Am J Clin Nutr 2011;94:701–8. 62. Hussain A, Nookaew I, Khoomrung S, Andersson L, Larsson I, Hulthen L, Jansson N, Jakubowicz R, Nilsson S, Sandberg AS, Nielsen J, Holmang A. A maternal diet of fatty fish reduces body fat of offspring compared with a maternal diet of beef and a post-weaning diet of fish improves insulin sensitivity and lipid profile in adult C57BL/6 male mice. Acta Physiol (Oxf) 2013;209:220–34. 63. Joshi S, Rao S, Golwilkar A, Patwardhan M, Bhonde R. Fish oil supplementation of rats during pregnancy reduces adult disease risks in their offspring. J Nutr 2003;133:3170–4. 64. Ibrahim A, Ghafoorunissa, Basak S, Ehtesham NZ. Impact of maternal dietary fatty acid composition on glucose and lipid metabolism in male rat offspring aged 105 d. Br J Nutr 2009;102:233–41. 65. López-Soldado I, Ortega-Senovilla H, Herrera E. Fish oil intake during pregnancy and lactation in rats has different long-term effects on glucoseinsulin relationships in male pups depending on their age. Sci Pages Diabetol 2017;1:1–5. 66. Siemelink M, Verhoef A, Dormans JA, Span PN, Piersma AH. Dietary fatty acid composition during pregnancy and lactation in the rat programs growth and glucose metabolism in the offspring. Diabetologia 2002;45:1397–403. 67. de Alwis NM, Day CP. Non-alcoholic fatty liver disease: the mist gradually clears. J Hepatol 2008;48(Suppl. 1):S104–12. 68. Neuschwander-Tetri BA. Nonalcoholic steatohepatitis and the metabolic syndrome. Am J Med Sci 2005;330:326–35. 69. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease—meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73–84. 70. Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics 2006;118:1388–93. 71. Welsh JA, Karpen S, Vos MB. Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, 1988-1994 to 2007-2010. J Pediatr 2013;162:496–500.e491. 72. Collaboration NCDRF. Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128.9 million children, adolescents, and adults. Lancet 2017;390:2627–42. 73. Malaguarnera M, Di Rosa M, Nicoletti F, Malaguarnera L. Molecular mechanisms involved in NAFLD progression. J Mol Med (Berl) 2009;87:679–95. 74. Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology 1998;114:842–5.
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75. Kucera O, Cervinkova Z. Experimental models of non-alcoholic fatty liver disease in rats. World J Gastroenterol 2014;20:8364–76. 76. Alkhouri N, Carter-Kent C, Feldstein AE. Apoptosis in nonalcoholic fatty liver disease: diagnostic and therapeutic implications. Expert Rev Gastroenterol Hepatol 2011;5:201–12. 77. Brumbaugh DE, Friedman JE. Developmental origins of nonalcoholic fatty liver disease. Pediatr Res 2014;75:140–7. 78. Adams LA. Nonalcoholic fatty liver disease and diabetes mellitus. Endocr Res 2007;32:59–69. 79. Charlton M, Sreekumar R, Rasmussen D, Lindor K, Nair KS. Apolipoprotein synthesis in nonalcoholic steatohepatitis. Hepatology 2002;35: 898–904. 80. Letteron P, Sutton A, Mansouri A, Fromenty B, Pessayre D. Inhibition of microsomal triglyceride transfer protein: another mechanism for druginduced steatosis in mice. Hepatology 2003;38:133–40. 81. Barker DJ, Bull AR, Osmond C, Simmonds SJ. Fetal and placental size and risk of hypertension in adult life. BMJ 1990;301:259–62. 82. Barker DJ. A new model for the origins of chronic disease. Med Health Care Philos 2001;4:31–5. 83. Hales CN, Barker DJ. The thrifty phenotype hypothesis. Br Med Bull 2001;60:5–20. 84. Poston L. Gestational weight gain: influences on the long-term health of the child. Curr Opin Clin Nutr Metab Care 2012;15:252–7. 85. Sookoian S, Gianotti TF, Burgueno AL, Pirola CJ. Fetal metabolic programming and epigenetic modifications: a systems biology approach. Pediatr Res 2013;73:531–42. 86. Kim SY, Dietz PM, England L, Morrow B, Callaghan WM. Trends in pre-pregnancy obesity in nine states, 1993-2003. Obesity (Silver Spring) 2007;15:986–93. 87. Dabelea D, Snell-Bergeon JK, Hartsfield CL, Bischoff KJ, Hamman RF, McDuffie RS, Kaiser Permanente of Colorado GDMSP. Increasing prevalence of gestational diabetes mellitus (GDM) over time and by birth cohort: Kaiser Permanente of Colorado GDM Screening Program. Diabetes Care 2005;28:579–84. 88. Symonds ME, Mostyn A, Pearce S, Budge H, Stephenson T. Endocrine and nutritional regulation of fetal adipose tissue development. J Endocrinol 2003;179:293–9. 89. Bruce KD, Cagampang FR, Argenton M, Zhang J, Ethirajan PL, Burdge GC, Bateman AC, Clough GF, Poston L, Hanson MA, McConnell JM, Byrne CD. Maternal high-fat feeding primes steatohepatitis in adult mice offspring, involving mitochondrial dysfunction and altered lipogenesis gene expression. Hepatology 2009;50:1796–808. 90. Gregorio BM, Souza-Mello V, Carvalho JJ, Mandarim-de-Lacerda CA, Aguila MB. Maternal high-fat intake predisposes nonalcoholic fatty liver disease in C57BL/6 offspring. Am J Obstet Gynecol 2010;203(495):e491–498. 91. Elahi MM, Cagampang FR, Mukhtar D, Anthony FW, Ohri SK, Hanson MA. Long-term maternal high-fat feeding from weaning through pregnancy and lactation predisposes offspring to hypertension, raised plasma lipids and fatty liver in mice. Br J Nutr 2009;102:514–9. 92. McCurdy CE, Bishop JM, Williams SM, Grayson BE, Smith MS, Friedman JE, Grove KL. Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates. J Clin Investig 2009;119:323–35. 93. Clayton ZE, Vickers MH, Bernal A, Yap C, Sloboda DM. Early life exposure to fructose alters maternal, fetal and neonatal hepatic gene expression and leads to sex-dependent changes in lipid metabolism in rat offspring. PLoS One 2015;10:e0141962. 94. Toop CR, Muhlhausler BS, O’Dea K, Gentili S. Impact of perinatal exposure to sucrose or high fructose corn syrup (HFCS-55) on adiposity and hepatic lipid composition in rat offspring. J Physiol 2017;595:4379–98. 95. Oben JA, Patel T, Mouralidarane A, Samuelsson AM, Matthews P, Pombo J, Morgan M, McKee C, Soeda J, Novelli M, Poston L, Taylor P. Maternal obesity programmes offspring development of non-alcoholic fatty pancreas disease. Biochem Biophys Res Commun 2010;394:24–8. 96. Bouanane S, Merzouk H, Benkalfat NB, Soulimane N, Merzouk SA, Gresti J, Tessier C, Narce M. Hepatic and very low-density lipoprotein fatty acids in obese offspring of overfed dams. Metabolism 2010;59:1701–9. 97. Pereira TJ, Fonseca MA, Campbell KE, Moyce BL, Cole LK, Hatch GM, Doucette CA, Klein J, Aliani M, Dolinsky VW. Maternal obesity characterized by gestational diabetes increases the susceptibility of rat offspring to hepatic steatosis via a disrupted liver metabolome. J Physiol 2015;593:3181–97. 98. Bayol SA, Simbi BH, Fowkes RC, Stickland NC. A maternal “junk food” diet in pregnancy and lactation promotes nonalcoholic Fatty liver disease in rat offspring. Endocrinology 2010;151:1451–61. 99. Schaefer-Graf UM, Meitzner K, Ortega-Senovilla H, Graf K, Vetter K, Abou-Dakn M, Herrera E. Differences in the implications of maternal lipids on fetal metabolism and growth between gestational diabetes mellitus and control pregnancies. Diabet Med 2011;28:1053–9. 100. Herrera E, Ortega-Senovilla H. Implications of lipids in neonatal body weight and fat mass in gestational diabetic mothers and non-diabetic controls. Curr Diabetes Rep 2018;18:1–13. 101. Lorenzo M, Benito M, Caldes T, Medina JM. Regulation of lipogenesis in vivo by glucose availability and insulin secretion in maternal and foetal tissues during late gestation in the rat. Effect of glucose intubation, streptozotocin-induced diabetes and starvation. Biochem J 1983;216:695–9. 102. Herrera E. Lipid metabolism in pregnancy and its consequences in the fetus and newborn. Endocrine 2002;19:43–55. 103. Poissonnet CM, Burdi AR, Bookstein FL. Growth and development of human adipose tissue during early gestation. Early Hum Dev 1983;8:1–11. 104. Bernstein IM, Goran MI, Amini SB, Catalano PM. Differential growth of fetal tissues during the second half of pregnancy. Am J Obstet Gynecol 1997;176:28–32. 105. Seet EL, Yee JK, Jellyman JK, Han G, Ross MG, Desai M. Maternal high-fat-diet programs rat offspring liver fatty acid metabolism. Lipids 2015;50:565–73. 106. Kjaergaard M, Nilsson C, Rosendal A, Nielsen MO, Raun K. Maternal chocolate and sucrose soft drink intake induces hepatic steatosis in rat offspring associated with altered lipid gene expression profile. Acta Physiol (Oxf) 2014;210:142–53. 107. Masi LN, Rodrigues AC, Curi R. Fatty acids regulation of inflammatory and metabolic genes. Curr Opin Clin Nutr Metab Care 2013;16:418–24.
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108. Yamamoto K, Itoh T, Abe D, Shimizu M, Kanda T, Koyama T, Nishikawa M, Tamai T, Ooizumi H, Yamada S. Identification of putative metabolites of docosahexaenoic acid as potent PPARgamma agonists and antidiabetic agents. Bioorg Med Chem Lett 2005;15:517–22. 109. Goto T, Kim YI, Takahashi N, Kawada T. Natural compounds regulate energy metabolism by the modulating the activity of lipid-sensing nuclear receptors. Mol Nutr Food Res 2013;57:20–33. 110. Videla LA, Pettinelli P. Misregulation of PPAR functioning and its pathogenic consequences associated with nonalcoholic fatty liver disease in human obesity. PPAR Res 2012;2012:107434. 111. Fernandez V, Tapia G, Videla LA. Recent advances in liver preconditioning: thyroid hormone, n-3 long-chain polyunsaturated fatty acids and iron. World J Hepatol 2012;4:119–28. 112. Valenzuela R, Espinosa A, Gonzalez-Manan D, D’Espessailles A, Fernandez V, Videla LA, Tapia G. N-3 long-chain polyunsaturated fatty acid supplementation significantly reduces liver oxidative stress in high fat induced steatosis. PLoS One 2012;7:e46400. 113. Dossi CG, Tapia GS, Espinosa A, Videla LA, D’Espessailles A. Reversal of high-fat diet-induced hepatic steatosis by n-3 LCPUFA: role of PPARalpha and SREBP-1c. J Nutr Biochem 2014;25:977–84. 114. Shapiro H, Tehilla M, Attal-Singer J, Bruck R, Luzzatti R, Singer P. The therapeutic potential of long-chain omega-3 fatty acids in nonalcoholic fatty liver disease. Clin Nutr 2011;30:6–19. 115. Thorsdottir I, Birgisdottir BE, Halldorsdottir S, Geirsson RT. Association of fish and fish liver oil intake in pregnancy with infant size at birth among women of normal weight before pregnancy in a fishing community. Am J Epidemiol 2004;160:460–5. 116. Chatzi L, Stratakis N. Maternal fish intake during pregnancy and effects on the offspring. In: Rajendram R, Preedy VR, Patel VB, editors. Diet, nutrition, and fetal programming. Cham: Humana Press; 2017. p. 241–60.
Fish Oil Supplements During Perinatal Life: Impact on the Liver of Offspring Emilio Herrera, Encarnación Amusquivar Department of Biochemistry and Chemistry, University San Pablo CEU, Madrid, Spain
1. INTRODUCTION The fetus uses fatty acids as structural components, a source of energy, precursors of bioactive compounds, and regulators of transcription factors. Of the different fatty acids, the polyunsaturated fatty acids (PUFAs) play a key function in intrauterine and postnatal development. The essential fatty acids (EFAs), linoleic acid (LA, 18:2 n-6), and α-linolenic acid (ALA, 18:3 n-3), or their long-chain PUFA (LCPUFA) derivatives must be obtained from external sources, either from the diet or by supplementation. ALA and LA are the biosynthetic precursors (by elongation and desaturation) of the n-3 and n-6 LCPUFAs, respectively. In adults, none of the LCPUFAs are absolute dietary requirements, because they can be synthesized from the EFA precursors; in the fetus, term and preterm neonates, however, synthesis of LCPUFA from EFA is very limited and their plasma concentrations mainly depend on the maternal supply. It is well known that maternal concentrations of LCPUFAs during pregnancy correlate with those in the fetus and newborn. Furthermore, there is evidence to suggest that in humans, n-3 LCPUFAs have positive impacts on health such as the reduction of risk factors for several diseases, including nonalcoholic fatty liver disease (NAFLD). These considerations have been used to justify the advice that, during pregnancy and lactation, the maternal diet should contain an appropriate amount of fish or be supplemented with fish oil, which is rich in eicosapentaenoic acid (EPA, 20:5 n-3) and docosahexaenoic acid (DHA, 22:6 n-3). Moreover, fatty acids may alter the epigenome during the perinatal stage, with variable long-term metabolic and gene function consequences when adulthood is reached. This chapter reviews the role of fatty acids during perinatal development and the potential protective role of fish oil supplementation during the perinatal stages of NAFLD development.
2. ROLE OF FATTY ACIDS IN FETAL DEVELOPMENT From the onset of gestation, the human embryo and the fetus require PUFA for their normal development. Until approximately 25 weeks of gestation, fetal accumulation of specific fatty acids is relatively small, but increases logarithmically with gestational age to reach its maximal accretion rate during the last 5 weeks of intrauterine life.1,2 It has been estimated in Western populations, in the late weeks of pregnancy, that the PUFA with the highest rate of whole body fetal accretion is LA followed by two LCPUFAs, arachidonic acid (AA, 20:4 n-6) and DHA.3 At term and throughout the first 2 years of life, DHA is the fatty acid present in the highest proportion in the phospholipids of neuronal membranes of the cerebral cortex and in the retinal photoreceptors.4 During pregnancy and the neonatal period, in the fetus and newborn, both retinal function and learning ability become permanently impaired if the accumulation of DHA is insufficient,5 and low levels of DHA in premature infants have been shown to affect their eye and brain functions.6,7 Visual acuity has been shown to improve in preterm infants fed formula containing a DHA supplement.8 These and other related findings have motivated dietary supplementation with fish oil, which is rich in DHA and its metabolic precursor, EPA, in pregnant women, although the findings are not yet conclusive (see below). Fatty acid oxidation also seems to play a major role in fetal development. The fetus has traditionally been considered to be dependent on glucose oxidation for energy production. However, several recessively inherited disorders in genes of the mitochondrial fatty acid oxidation (MFAO) system have been associated with prematurity, intrauterine growth retardation, and hepatic encephalopathy.9 Furthermore, it has been shown in several tissues of the human fetus that there is substantial mRNA expression and activity of MFAO enzymes.10 These findings have led to the proposal that fatty acid oxidation plays Dietary Interventions in Liver Disease. https://doi.org/10.1016/B978-0-12-814466-4.00024-0 Copyright © 2019 Elsevier Inc. All rights reserved.
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an important role in the human fetus, contributing greatly to its development.11 In animal studies, disturbances of the MFAO pathway have also been shown to lead to fetal demise and fetal growth retardation, and to reduce fertility.12 It may therefore be concluded that fatty acids play a key role in fetal development, their oxidation playing an important role as a source of energy also being essential. This is particularly so in case of the LCPUFAs, which are precursors of bioactive compounds and are involved in the structure and function of the nervous system and retina.2 Although the fetus is able to synthesize saturated and monounsaturated fatty acids,13 the LCPUFAs are of maternal origin; they are the main fatty acids crossing the placenta1 and are probably the preferred oxidative substrate for the fetus, being essential therefore in its development.2
3. FATTY ACIDS AND EPIGENETICS Epigenetics can be defined as a hereditable DNA activity that depends on its chemical modifications and adjacent regulatory proteins that are independent of the DNA sequence.14,15 Epigenetic markers include the addition to DNA of a methyl group, which is covalently attached to a cytosine of a CpG dinucleotide. The degree of DNA methylation within the genome is cell and tissue specific and is usually associated with decreased gene expression. On the other hand, hypomethylation is associated with increased gene expression.16 Another epigenetic marker is the modification of histones which, as well as packaging DNA, play a significant role in posttranslational modifications of amino acids, such as acetylation, methylation, or phosphorylation.17 An additional epigenetic marker is the activity of noncoding RNAs such as microRNAs, interference RNAs, long-chain RNAs, and antisense RNAs.18,19 These noncoding RNAs regulate several cellular processes by posttranscriptionally regulating gene expression through their pairing to the messenger RNA.20 Because of the influence of maternal metabolism on embryo development during pregnancy and the plasticity of epigenetic regulation during development, the impact of nutrition during early life has been linked to health and diseases in later life.21 There is now emerging evidence that dietary fatty acids and fats during the perinatal period can alter the epigenome, and it is well established that modifying the amount and quality of fatty acids, especially the n-3 PUFA, in the maternal diet may affect the epigenetic outcomes in the offspring.22 The n-3 PUFAs have been shown to have antilipidemic effects through the promotion of lipolysis and fatty acid oxidation and the inhibition of lipogenesis and circulating triacylglycerol (TAG) concentrations, as well as antiatherogenic, antiinflammatory, and anti-cell-development properties in humans. Although prospective observational studies have shown inconsistent associations between dietary or circulating n-3 LCPUFAs and the risk of coronary heart disease or the risk of all-cause mortality, metaanalysis of randomized controlled trials involving a sufficient number of participants has suggested that they are inversely associated with both coronary heart disease23 and all-cause mortality.24 These effects are brought about by the ability of n-3 LCPUFAs to regulate the expression of different genes, by changing the methylation at the cytosine in the CpG islands of DNA25,26 or by modulating the expression of some noncoding RNAs,27 thereby modifying the epigenome. In this regard, it has been shown that certain fatty acids could modulate the expression of miRNA in different cell types in vitro.28–30 The evidence for these effects in vivo is limited;31,32 but we fed pregnant rats with isoenergetic diets which contained 9% oils with different fatty acid compositions from conception to day 12 of pregnancy, after which they were fed with a standard diet until the end of the study. In the liver of a 12-month-old male offspring, the expression of miRNAs such as miR-215, miR-10b, miR-377-3p, and miR-192, among others, was found to be differentially modulated by the different fatty acids consumed by the dams during just the first half of pregnancy.33 A decrease in the expression of hepatic miRNAs and an increase in the expression of target genes related to insulin signaling were found in the offspring from dams given the fish oil supplemented diet during just the first half of pregnancy when compared with those given either soybean-, olive-, linseed- or palm-oil supplements.33 These findings clearly fit with both the reduced fat accretion and the age-related decline in insulin sensitivity found in 12-month-old male offspring of rats given the fish oil diet during early pregnancy.34 Such an effect was not, however, found in female offspring, which agrees with the reported significant differences in the way human males and females metabolize and store n-3 PUFAs26,35 as well as the gender-dependent global genomic DNA methylation36 and infant epigenome after prenatal DHA supplementation.37 The precise mechanism(s) underlying the epigenetic effects induced by a particular type of fatty acid is not completely elucidated. Nevertheless, this area of research—into how dietary fatty acids can modify the epigenome—is both valid and important because it will provide new insights into the effects of dietary fatty acids on development, metabolism and risk of disease, and the mechanisms thereof.
4. FISH OIL SUPPLEMENTS DURING PREGNANCY Although it is known that, at the time of birth, human newborns can synthesize both AA and DHA from their respective EFA, LA or ALA, respectively, the process is limited.38,39 Therefore, because those LCPUFA are a requirement for appropriate fetal development during the intrauterine life, they must come from maternal circulation by placental transfer.2
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Despite the molecular mechanism of this process not being completely understood,40 it is known to occur at a high rate.41 Whereas the proportion of both AA and DHA in human maternal circulation declines during late pregnancy, their percentage in the neonate at birth is higher than that in the mother.42 It has been shown in both humans43 and rats13 that plasma concentrations of LCPUFAs in maternal circulation correlate with those in the fetus. On the basis of these and other similar findings, the current advice is that maternal diet should be supplemented with fish oil during the last months of pregnancy. However, under these circumstances, low levels of AA are frequently found in the mother and the fetus, both in humans44,45 and rats.46,47 This is probably a consequence of the known effects of the two main LCPUFAs present in fish oil, DHA and EPA, inhibiting Δ5- and Δ6-desaturases, which are rate-limiting enzymes for AA synthesis from its essential precursor, LA. This is of particular importance for intrauterine growth and development because plasma concentrations of AA have been correlated to body weight in preterm infants and early human growth, and therefore an adverse effect of fish oil supplementation related to low plasma AA has been proposed.48,49 Although in many countries fish oil is currently the most common dietary supplement during pregnancy, with the exception of vitamins and minerals, the evidence for the benefits to the mother or the offspring is not yet well established. Indeed, randomized controlled trials have produced contradictory results.50 There have been many clinical trials designed to determine the potential benefits of fish oil supplementation during pregnancy, but the evidence is still weak. Fish oil supplements during pregnancy have been shown not to prevent preterm birth problems (including reductions in the number of offspring in rats) or to bring about improvements in neonatal outcome.51 It has been reported that they do not prevent preeclampsia or intrauterine growth restriction50 or reduce the risk of gestational diabetes and related pathologies.52 Even in rats it has been shown that excessive consumption of fish oil during pregnancy and lactation causes adverse effects on newborn body weight and neurological development.46 In humans, it has been shown that oxidative stress during pregnancy is associated to adverse effects to the mother and the offspring.53,54 The large number of double bonds in LCPUFA make it prone to oxidation, producing a variety of lipid peroxides, and therefore the intake of oxidized fish oil may increase lipid peroxidation and reduce antioxidant capacity. It has been proposed that the variable response to fish oil supplements during the periuterine phase could be related to its degree of oxidation because commercial preparations have been shown to exceed the recommended levels of oxidation markers as well as not meeting the content of n-3 LCPUFA claimed on the label.55 Studies in humans56,57 and in experimental animals58 have shown that prenatal and early postnatal dietary fatty acids, particularly PUFA, may affect the development of the fetus and newborn to have programming effects in the future by altering the development of diseases such as obesity, diabetes, cancer, cardiovascular diseases, or liver disorders in adults. The knowledge of programming effects from fish oil intake during pregnancy, lactation, or both in humans is limited. It has been shown in children that increased n-3 LCPUFA status during pregnancy causes lower adiposity59 and that the intake of cod liver oil during pregnancy reduces the risk of type 1 diabetes.60 There are also reports where daily supplementation with fish oil during the last trimester of pregnancy was not associated with either adiposity or insulin sensitivity values in 19-year-old offspring.61 The studies on long-term effects of fish oil intake during the perinatal stage in experimental animals are also scarce and variable, results showing that the dose and time window of supplementation is of importance.62–64 In offspring of rats fed with a diet containing 10% fish oil, compared with those fed the same diet but containing 10% olive oil, we have found that whereas at 2 months of age insulin sensitivity was increased, at 4 months no differences were found, but at 18 months a decreased insulin sensitivity was found in the fish oil group.65 However, by feeding rats with isocaloric diets containing 9% of fat based on soybean, olive, fish, linseed, or palm oil during just the first 12 days of pregnancy (roughly first half of pregnancy) and standard laboratory diet onward, we found that male pups at 12 months of age of those from the fish oil group have decreased lumbar adipose tissue weight and an increased insulin sensitivity index compared with those of the other groups. These same variables did not differ, however, between the groups in 12-month-old female offspring.34 These findings differ from those of Siemelink et al.66 in offspring of dams given a diet containing 18% fish oil from 2 weeks prior pregnancy and until the end of lactation, showing no effect on insulin sensitivity at 12 weeks of age, which again points out the importance of dose and time window of the fish oil supplement during pregnancy. From studies in rats, it seems that a moderate amount of fish oil intake during the first half of pregnancy rather than high doses are needed to reduce insulin resistance and adipose tissue mass in the adult male offspring but not in females.34 Because the potential change in the DNA marker in the embryo caused by maternal fish oil intake occurred during early pregnancy before sex differentiation of the gonads, it appears that differential hormonal environment in adult males versus females is responsible for the different gender responses of adult insulin sensitivity to the maternal fish oil diet intake. The mechanism underlying these effects is epigenetic and could be explained in part by the influence on miRNA expression33 as stated above.
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5. PREVALENCE AND PATHOGENIC ASPECTS OF NONALCOHOLIC FATTY LIVER DISEASE NAFLD is rapidly becoming the most common cause of chronic liver disease in the Western world.67 It represents a wide spectrum of diseases, including hepatocellular steatosis, steatohepatitis, and cirrhosis and is characterized by an abnormal accumulation of fat in the liver in patients with mild or absent alcohol ingestion.68 It has an increasing importance because of its high prevalence, which is estimated to be around 25% of the adult population in the world.69 It is also known that NAFLD is the most common form of liver disease in children and adolescents,70 its prevalence having more than doubled in the last two decades71 and has increased 10-fold since 1975.72 NAFLD patients are generally asymptomatic with mild, fluctuating elevations in liver enzymes but can progress to nonalcoholic steatohepatitis (NASH), fibrosis, and ultimately cirrhosis, which may progress to hepatocellular carcinoma.73 NAFLD is an umbrella term for a range of liver conditions ranging from simple steatosis at the lower end to NASH at the most severe end. In fact, some patients with simple steatosis progress to NASH, and according to the “two-hit” theory, proposed by Day and James in 1998,74 liver steatosis sensitizes hepatocytes to the second hit. This second insult may be caused by increased oxidative stress capable of initiating lipid peroxidation, mitochondrial dysfunction, cytokine or adipokine imbalance, lipotoxicity of nonesterified fatty acids (NEFAs), hepatic accumulation of cholesterol, and the activation of innate immunity.75 The main difference between simple steatosis and NASH is the degree of hepatocyte injury and apoptosis. Increased apoptosis is thought by some authors to be the third hit involved in NAFLD pathogenesis.76 Like adults, children with NAFLD can progress to cirrhosis and end-stage liver disease.77 The pathogenesis of NAFLD in humans is very complex and not yet fully understood, having a variety of risk factors such as nutritional habits, physical inactivity, chronic stress, and lifestyle, apart from genetic susceptibility. There is a great association between obesity, metabolic syndrome, insulin resistance, type 2 diabetes, and NAFLD,68,78 and the increases in the prevalence of all of them are strongly linked to changes in dietary habits. An accumulation of TAGs in liver is a characteristic of NAFLD. These TAGs are formed in hepatocytes by the esterification of the active forms of fatty acids (acyl-CoA) and glycerol (glycerol-3-phosphate). Fatty acids in liver arise from three sources: (1) endogenous lipogenesis de novo, (2) diet, and (3) adipose tissue lipolysis, which corresponds to the hydrolysis of accumulated TAGs to NEFAs and glycerol, and the release of NEFA into blood to reach the liver. In the liver, fatty acids may be broken down by β-oxidation or reesterified to form TAGs again that may be subsequently stored as lipid droplets or be exported into the circulation in the form of very low–density lipoproteins (VLDL). These lipoproteins are formed in the liver by the incorporation of TAG into apolipoprotein B–containing structures by the action of the microsomal TAG transfer protein (MTP). Hepatic TAG accumulation can therefore result from the imbalance of increased NEFA arrival and subsequent reesterification, increased lipogenesis, decreased fatty acid oxidation, decreased VLDL export, or a combination of these events. A reduction of MTP activity or apo B synthesis and VLDL secretion impairs hepatic TAG export and favors their hepatic accumulation.79,80
6. FETAL PROGRAMMING ORIGINS OF NAFLD The first report of an altered intrauterine environment resulting in low-birth-weight newborns associated with the risk of a number of diseases including obesity, diabetes, and cardiovascular risk in adulthood was by Barker and coworkers81–83 and was later extended to large-for-gestational-age babies.84 The concept of fetal programming refers to the conditions in utero or the insults during intrauterine life, such as the nutrients the fetus receives during gestation, that play an important role in health during the whole life of an individual. There is now evidence that fetal metabolic programming caused by the intrauterine nutritional environment is influenced by epigenetic changes that involve changes in gene expression caused by chromatin remodeling, such as methylation of DNA and histone modifications, as described above for fatty acids.85 The increased prevalence of maternal obesity and gestational diabetes mellitus during the last half century86,87 are thought to have increased the risk of juvenile obesity and other metabolic diseases, including NAFLD in the offspring,77 which as stated above is the most common chronic human liver disease. The mechanism(s) whereby excess maternal nutrition affects fetal development is still poorly understood, but it has been proposed that immature—and even lack of—adipose tissue in most species until relatively late in pregnancy may be responsible for the fetus being vulnerable to steatosis. This includes humans, where the fetal adipose tissue deposition occurs primarily over the final third of gestation88 and may not be sufficient to act as a buffer for excessive transplacental delivery of lipid, as can be the case when the mother is obese or hyperlipidemic. Several experimental studies carried out in rodents89–91 and in nonhuman primates (NHP)92 have shown that maternal obesogenic diets with a high-fat content can program hepatic steatosis (NAFLD) or even NASH in the offspring. Also, an excess of sucrose or fructose consumption during pregnancy, which is associated with the development of type 2 diabetes, obesity, and hyperlipidemia, has been shown in rodents to cause a fatty liver in the offspring.93,94 Moreover, when diets
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containing high fat and high sugar, like the so-called cafeteria or junk food diets, are applied during pregnancy, young offspring have consistently shown signs of NAFLD,95–97 and these signs were exacerbated when the offspring were exposed to junk food during pregnancy, lactation, and after weaning, showing hepatic steatosis, hepatic ballooning, oxidative stress, and altered expression of genes involved in glucose and lipid metabolism.98 In pregnant NHP the fetal liver of those chronically fed a high-fat diet (HFD) have been shown to have increased TAG concentrations and evidence of oxidative stress that are consistent with the development of NAFLD.92 Not all the NHP given the HFD developed obesity and insulin resistance, but all fetal offspring of HFD mothers showed all the signs of early NAFLD at the third trimester of intrauterine life, and the increased liver TAG concentration persisted until at least 180 days postnatally. The mechanisms by which maternal obesity or the ingestion of high-calorie processed food during the perinatal stages can lead to NAFLD development in the fetus and later offspring are not completely known. It may be driven in part by an increased delivery of maternal nutrients to the fetus, especially lipids. Under those conditions, maternal hyperlipidemia becomes exaggerated. Fatty acids cross the placenta with difficulties, in spite of several intrinsic factors within the placenta, but their quantitative maternal–fetal transfer is mainly driven by the gradient.40 In studies in normal healthy women designed to determine the contribution of nutrients in maternal circulation to fetal metabolic variables, we showed that maternal glucose, NEFA, and glycerol, but not TAG, correlate positively and linearly with those in cord blood.99 As reviewed recently,100 under these healthy conditions, maternal glucose reaching the fetus as a result of its maternal/fetal gradient is used by fetal liver partially to synthesize fatty acid (i.e., de novo lipogenesis) and for subsequent esterification of acyl-CoA with glycerol-3-phosphate for the synthesis of TAG. Maternal oral glucose load in rats has been shown to increase fetal liver lipogenesis,101 and in mice maternal fat intake has been shown to upregulate the hepatic expression of genes involved in hepatic TAG synthesis.89 Taking into account the above-mentioned maternal–fetal metabolic interactions, we propose the picture shown in Fig. 24.1 to interpret the fetal induction of NAFLD under conditions of enhanced maternal/ fetal glucose gradient and maternal hyperlipidemia, as it is often the case of maternal obesity or diabetic conditions. The TAGs synthesized in fetal liver from maternal glucose crossing the placenta are pooled with those also formed in fetal liver from the plasma NEFA that are derived from placental transfer of fatty acids. Those latter fatty acids are carried in maternal circulation associated to lipoproteins in their esterified form102 and are hydrolyzed in the placenta by the action of placental lipases (endothelial lipase, lipoprotein lipase, and phospholipase A2) and released as NEFA to fetal circulation. During late gestation, fetal liver TAGs are released into the circulation in the form of TAG-rich lipoproteins that are hydrolyzed by adipose tissue lipoprotein lipase, thus facilitating the uptake and intracellular reesterification of the lipolytic products to form TAG for their accumulation in adipose tissue. Over this picture, there are at least two aspects that should be taken into account to understand the increase of liver TAG under conditions of exaggerated maternal hyperlipidemia: (1) The excess of TAG liver accumulation is mainly the result of increased liver uptake of circulating NEFA derived from maternal lipid transfer and (2) in humans, fetal adipogenesis takes place from around the 14th week of gestation,103 but fetal fat accretion does not accelerate until the last weeks of gestation.104 It has been hypothesized that, under conditions of excess nutrition such as maternal high-fat diet, obesity, and gestational diabetes mellitus, especially during early pregnancy, the fetus utilizes the liver for energy storage.77,92 Therefore, increased placental transfer of maternal fuels such as glucose and fatty acids is responsible for increased hepatic TAG storage in the fetus, especially when sufficient adipose tissue is not available as a storage buffer to handle excess nutrition.
7. POTENTIAL PROTECTIVE ROLE OF FISH OIL IN THE NAFLD DEVELOPMENT As well as the changes reported above, it is known that an excess of dietary lipids during pregnancy may impact several pathways in fatty acid metabolism that could contribute to their fetal metabolic programming effect. In fact, it is known that development of NAFLD in rats is associated with an increase in the expression of genes that take part in lipogenesis (i.e., acetyl CoA carboxylase [ACC], fatty acid synthase [FAS], and stearoyl-CoA desaturase-1 [SCD1]) or regulate this pathway (i.e., sterol regulatory element-binding protein 1c [SREBP-1c] and liver X receptor-α [LXR α])105 as well as decrease the expression of genes associated with hepatic fatty acid oxidation such as peroxisome proliferator–activated receptor α (PPAR-α), carnitine palmitoyl transferase-1 (CPT-1), and mitochondrial matrix proteins.106 The n-3 LCPUFAs present in fish oil (EPA and DHA) have major functions in the regulation of hepatic lipid metabolism.107 They decrease de novo lipogenesis by inhibiting the expression of the transcription factor SREBP-1c as well as the transcription of lipogenic genes. They also increase liver uptake of NEFA and fatty acid oxidation through the activation of both PPARγ108 and PPARα109,110 as well as downregulating the expression of proinflammatory genes.111 These effects of fish oil have been considered together with other actions to be a viable therapeutic strategy for NAFLD. In fact, there are studies showing that fish oil supplementation to mice already consuming an HFD, and consequently developing liver steatosis, results in reduced hepatic lipid content, increased antioxidant responses, increased insulin sensitivity, favored
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FIGURE 24.1 Schematic picture of the proposed mechanism by which maternal obesity or hyperlipidemic and hyperglycemic conditions can lead to the development of nonalcoholic fatty liver disease in the fetus. Details are reported in the text. EL, endothelial lipase; LPL, lipoprotein lipase; NEFA, nonesterified fatty acids; PL-A2, phospholipase A2; TAG, triacylglycerols.
fatty acid oxidation as a result of PPARα activation, downregulation of expression of SREBP-1c, and antiinflammatory effects.112,113 Furthermore, a literature search of preclinical and clinical studies has shown an ameliorative effect of dietary supplements of fish oil or purified n-3 LCPUFAs in NAFLD, by reducing hepatic lipid content, arriving at the conclusion that they appear safely to reduce nutritional fatty liver disease in adults.114 In spite of these positive results, some harmful effects of high maternal doses of fish oil or DHA supplements in women have also been reported,115 and recent reviews of the scientific literature have concluded that the association of maternal fish or fish oil consumption during pregnancy with child health outcomes has been largely inconsistent.42,50,116 Therefore, additional studies using different doses of fish oil supplements or natural sources of n-3 LCPUFAs and at different time intervals during perinatal life to determine their long-term health benefits in the offspring are warranted.
ACKNOWLEDGMENTS The authors thank Dr. Peter Dodds for editing and linguistic revision of the manuscript. Preparation of this chapter was carried out in part with grants from the Universidad San Pablo-CEU and the Fundación Ramón Areces (CIVP16A1835) of Spain.
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