Polymorphisms, de novo lipogenesis, and plasma triglyceride response following fish oil supplementation

Interindividual variability in the response of plasma triglyceride concentrations (TG) following fish oil consumption has been observed. Our objective was to examine the associations between single-nucleotide polymorphisms (SNPs) within genes encoding proteins involved in de novo lipogenesis and the relative change in plasma TG levels following a fish oil supplementation. Two hundred and eight participants were recruited in the greater Quebec City area. The participants completed a six-week fish oil supplementation (5 g fish oil/day: 1.9–2.2 g eicosapentaenoic acid and 1.1 g docosahexaenoic acid. SNPs within SREBF1, ACLY, and ACACA genes were genotyped using TAQMAN methodology. After correction for multiple comparison, only two SNPs, rs8071753 (ACLY) and rs1714987 (ACACA), were associated with the relative change in plasma TG concentrations (P= 0.004 and P= 0.005, respectively). These two SNPs explained 7.73% of the variance in plasma TG relative change following fish oil consumption. Genotype frequencies of rs8071753 according to the TG response groups (responders versus nonresponders) were different (P= 0.02). We conclude that the presence of certain SNPs within genes, such as ACLY and ACACA, encoding proteins involved in de novo lipogenesis seem to influence the plasma TG response following fish oil consumption. Interindividual variability in the response of plasma triglyceride concentrations (TG) following fish oil consumption has been observed. Our objective was to examine the associations between single-nucleotide polymorphisms (SNPs) within genes encoding proteins involved in de novo lipogenesis and the relative change in plasma TG levels following a fish oil supplementation. Two hundred and eight participants were recruited in the greater Quebec City area. The participants completed a six-week fish oil supplementation (5 g fish oil/day: 1.9–2.2 g eicosapentaenoic acid and 1.1 g docosahexaenoic acid. SNPs within SREBF1, ACLY, and ACACA genes were genotyped using TAQMAN methodology. After correction for multiple comparison, only two SNPs, rs8071753 (ACLY) and rs1714987 (ACACA), were associated with the relative change in plasma TG concentrations (P= 0.004 and P= 0.005, respectively). These two SNPs explained 7.73% of the variance in plasma TG relative change following fish oil consumption. Genotype frequencies of rs8071753 according to the TG response groups (responders versus nonresponders) were different (P= 0.02). We conclude that the presence of certain SNPs within genes, such as ACLY and ACACA, encoding proteins involved in de novo lipogenesis seem to influence the plasma TG response following fish oil consumption. In Canada, cardiovascular disease (CVD) is the second leading cause of mortality after cancer (1Statistics Canada. Leading Causes of Death in Canada. 2009. Accessed November 23, 2012. http://www.statcan.gc.ca/pub/84–215-x/2012001/hl-fs-eng.htm.Google Scholar). Many risk factors contribute to increase the risk of developing CVD. Among them, plasma triglyceride (TG) concentrations have been debated about whether they should be considered as an independent CVD risk factor. A review by Morisson et al. (2Morrison A. Hokanson J.E. The independent relationship between triglycerides and coronary heart disease.Vasc. Health Risk Manag. 2009; 5: 89-95PubMed Google Scholar) indicated that plasma TG concentrations are an independent risk factor of coronary events in individuals without previous history of coronary heart disease (CHD). Plasma TG concentrations was the parameter of the metabolic syndrome the most strongly and independently associated with myocardial infarction and stroke (3Ninomiya J.K. L'Italien G. Criqui M.H. Whyte J.L. Gamst A. Chen R.S. Association of the metabolic syndrome with history of myocardial infarction and stroke in the Third National Health and Nutrition Examination Survey.Circulation. 2004; 109: 42-46Crossref PubMed Scopus (659) Google Scholar). However, a recent meta-analysis has demonstrated no independent association between plasma TG concentrations and CVD risk (4Di Angelantonio A.E. Sarwar N. Perry P. Kaptoge S. Ray K.K. Thompson A. Wood A.M. Lewington S. Sattar N. Packard C.J. et al.Major lipids, apolipoproteins, and risk of vascular disease.JAMA. 2009; 302: 1993-2000Crossref PubMed Scopus (1964) Google Scholar). Still, the presence of high plasma TG concentrations is an important biomarker indicating alterations of lipid metabolism. Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been proven as an effective way to reduce plasma TG concentrations (5Singh A. Schwartzbard A. Gianos E. Berger J.S. Weintraub H. What should we do about hypertriglyceridemia in coronary artery disease patients?.Curr. Treat. Options Cardiovasc. Med. 2013; 15: 104-117Crossref PubMed Scopus (6) Google Scholar). However, a large interindividual variability has been observed in plasma TG concentration response following n-3 PUFA supplementation (6Madden J. Williams C.M. Calder P.C. Lietz G. Miles E.A. Cordell H. Mathers J.C. Minihane A.M. The impact of common gene variants on the response of biomarkers of cardiovascular disease (CVD) risk to increased fish oil fatty acids intakes.Annu. Rev. Nutr. 2011; 31: 203-234Crossref PubMed Scopus (53) Google Scholar, 7Caslake M.J. Miles E.A. Kofler B.M. Lietz G. Curtis P. Armah C.K. Kimber A.C. Grew J.P. Farrell L. Stannard J. et al.Effect of sex and genotype on cardiovascular biomarker response to fish oils: the FINGEN Study.Am. J. Clin. Nutr. 2008; 88: 618-629Crossref PubMed Scopus (133) Google Scholar, 8Cormier H. Rudkowska I. Paradis A.M. Thifault E. Garneau V. Lemieux S. Couture P. Vohl M.C. Association between polymorphisms in the fatty acid desaturase gene cluster and the plasma triacylglycerol response to an n-3 PUFA supplementation.Nutrients. 2012; 4: 1026-1041Crossref PubMed Scopus (46) Google Scholar). A decrease in de novo lipogenesis is one of a few pathways that could explain the n-3 PUFA plasma TG-lowering effects. Lipogenesis is strongly regulated by the transcription factor sterol regulatory element-binding transcription factor 1 (SREBF1) (9Eberle D. Hegarty B. Bossard P. Ferre P. Foufelle F. SREBP transcription factors: master regulators of lipid homeostasis.Biochimie. 2004; 86: 839-848Crossref PubMed Scopus (1004) Google Scholar). n-3 PUFA decrease the expression of SREBF1 (10Xu J. Teran-Garcia M. Park J.H. Nakamura M.T. Clarke S.D. Polyunsaturated fatty acids suppress hepatic sterol regulatory element-binding protein-1 expression by accelerating transcript decay.J. Biol. Chem. 2001; 276: 9800-9807Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar, 11Tanaka N. Zhang X. Sugiyama E. Kono H. Horiuchi A. Nakajima T. Kanbe H. Tanaka E. Gonzalez F.J. Aoyama T. Eicosapentaenoic acid improves hepatic steatosis independent of PPARalpha activation through inhibition of SREBP-1 maturation in mice.Biochem. Pharmacol. 2010; 80: 1601-1612Crossref PubMed Scopus (61) Google Scholar). SREBF1 regulates the activity of several lipogenic genes, such as ATP citrate lyase (ACLY) and acetyl-CoA carboxylase α (ACACA). ACLY is the primary enzyme responsible for the synthesis of acetyl-CoA in the cytosol (12Chypre M. Zaidi N. Smans K. ATP-citrate lyase: a mini-review.Biochem. Biophys. Res. Commun. 2012; 422: 1-4Crossref PubMed Scopus (148) Google Scholar). Acetyl-CoA may then be transformed by ACACA to malonyl-CoA, which is the first product in fatty acid biosynthesis (13Wakil S.J. Stoops J.K. Joshi V.C. Fatty acid synthesis and its regulation.Annu. Rev. Biochem. 1983; 52: 537-579Crossref PubMed Google Scholar). Only a few polymorphisms within these genes have been studied. SREBF1, gly952gly (rs2297508), has been associated with obesity, type 2 diabetes, and serum lipids (14Eberle D. Clement K. Meyre D. Sahbatou M. Vaxillaire M. Le G.A. Ferre P. Basdevant A. Froguel P. Foufelle F. SREBF-1 gene polymorphisms are associated with obesity and type 2 diabetes in French obese and diabetic cohorts.Diabetes. 2004; 53: 2153-2157Crossref PubMed Scopus (98) Google Scholar, 15Zhang Z. Gong R.R. Du J. Xiao L.Y. Duan W. Zhou X.D. Fang D.Z. Associations of the SREBP-1c gene polymorphism with gender-specific changes in serum lipids induced by a high-carbohydrate diet in healthy Chinese youth.Appl. Physiol. Nutr. Metab. 2011; 36: 226-232Crossref PubMed Scopus (11) Google Scholar, 16Grarup N. Stender-Petersen K.L. Andersson E.A. Jorgensen T. Borch-Johnsen K. Sandbaek A. Lauritzen T. Schmitz O. Hansen T. Pedersen O. Association of variants in the sterol regulatory element-binding factor 1 (SREBF1) gene with type 2 diabetes, glycemia, and insulin resistance: a study of 15,734 Danish subjects.Diabetes. 2008; 57: 1136-1142Crossref PubMed Scopus (43) Google Scholar), whereas a few single-nucleotide polymorphisms (SNP) within ACACA gene (rs1266175 and rs2229416) were associated with plasma TG concentrations after the intake of certain antipsychotic drugs (17Diaz F.J. Meary A. Arranz M.J. Ruano G. Windemuth A. de. Leon J. Acetyl-coenzyme A carboxylase alpha gene variations may be associated with the direct effects of some antipsychotics on triglyceride levels.Schizophr. Res. 2009; 115: 136-140Crossref PubMed Scopus (13) Google Scholar). The effects of SNPs within these genes on plasma TG concentrations have never been studied in the context of n-3 PUFA supplementation. Therefore, the aim of the present study was to examine the associations between polymorphisms in genes involved in the lipogenesis pathway and the plasma TG response following a marine n-3 PUFA supplementation. A total of 254 unrelated subjects were recruited to participate in this clinical trial from the greater Quebec City metropolitan area between September 2009 and December 2011 through advertisements in local newspapers as well as by electronic messages sent to university students/employees. It was determined that a group of 152 participants was sufficient to provide an 80% probability and a 5% significance level of detecting an anticipated difference of 0.25 mmol/l in plasma TG concentrations after six weeks of fish oil supplementation with a genetic variation occurring in a relatively low frequency (5%) of the population. To be eligible, subjects had to be nonsmokers and free of any thyroid or metabolic disorders requiring treatment, such as diabetes, hypertension, severe dyslipidemia, or coronary heart disease. Participants had to be between ages 18 and 50 years and with a body mass index (BMI) between 25 and 40 kg/m2. The subjects who had taken n-3 PUFA supplements during the six months preceding the study were excluded. A total of 210 subjects completed the n-3 PUFA supplementation period. However, plasma TG concentrations were available for 208 participants, and thus the analyses were conducted on 208 participants. The experimental protocol was approved by the of and clinical trial was was from the study a of two were by a to the from were to these and body the were the n-3 PUFA to two fish or to of fatty were and to n-3 PUFA such as some and were to consumption during the two were In subjects were to n-3 PUFA supplements as or any during the After the a n-3 PUFA for the six were to g of fish a total of g of fish oil g eicosapentaenoic acid and 1.1 g docosahexaenoic acid were in sufficient for six was from the of and by plasma fatty acid were to any during the study protocol and to and fish consumption as well as any effects. A was to the by a J. G. A. B. Lemieux S. and of an frequency for healthy and J. 2004; PubMed Google Scholar). is on available in Quebec and with that have between one and The subjects were they or during the Many of were for a of the by the subjects completed two and after the n-3 PUFA supplementation period. and and A on to the with some and a of these and on two and one were or and in intake were using Nutrition for 2011 by the Nutrition of and were according to the by the J.H. of T. A. In The Scholar) and were taken the as well as and after the n-3 PUFA supplementation. was as The after a and were from an were to individuals with metabolic who were excluded. Plasma was by g for and were and for Plasma total and plasma TG concentrations were using lipid analyses for plasma and PubMed Scopus Google Scholar, M. J. a of the to the serum and 5: PubMed Scopus Google Scholar). with was to and and then concentrations D. P. P. L. A. K. S. et of for in Chem. PubMed Scopus Google Scholar). 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Vohl M.C. Association between polymorphisms in the fatty acid desaturase gene cluster and the plasma triacylglycerol response to an n-3 PUFA supplementation.Nutrients. 2012; 4: 1026-1041Crossref PubMed Scopus (46) Google Scholar). were determined using SNPs were In an to the effects of the associated on or on D. D. in Biol. 4: PubMed Scopus Google Scholar), P. of different of and in gene Res. 15: PubMed Scopus Google Scholar, D. M. G. M. an to Res. 2009; PubMed Scopus Google Scholar), and C.K. A. Chen an and for and Res. PubMed Scopus Google Scholar) were was with the of using the genotype frequency for individuals of the was and of the were were To examine the difference between and for the plasma TG two groups were The group individuals in which plasma TG concentrations after the supplementation change in plasma TG The group individuals in which plasma TG concentrations change or increased change in plasma TG and the relative change in the of the participants were between the and with an and for and To the SNPs that were associated with the relative change in plasma TG the of was with and as To the effects of multiple the by et al. X. J. A multiple correction for genetic association using 2008; PubMed Scopus Google Scholar) was the of between SNPs and has been demonstrated as and with X. J. A multiple correction for genetic association using 2008; PubMed Scopus Google Scholar). the was from the were using the and the of effective independent was that the explain of the variation in as by et al. X. J. A multiple correction for genetic association using 2008; PubMed Scopus Google Scholar). The the correction to the significance which was as independent were considered To the the most associated with the relative change in plasma TG a with and only and with was and the was to the in the frequencies between and according to analyses were using of the study participants are in was 25 and lipids were Third of the National on and of in Scholar). of the study participants according to plasma TG response (responders versus nonresponders) are in the had concentrations and plasma TG concentrations After the the of increased that of had increased and plasma TG concentrations and whereas the was observed for These are with previous for a of participants from this I. Paradis A.M. Thifault E. P. O. Couture P. Lemieux S. Vohl M.C. in and between and to an n-3 polyunsaturated fatty acids Nutr. 2012; PubMed Scopus Google of the study participants insulin 0.25 are in a of the study participants according to plasma TG response and and for and the relative change in and for and 0.25 are and for and the relative change in and for and in a are are The for the fish oil supplementation was The had a of and for the the was (P= were observed in fatty acid plasma n-3 and between and The SNPs are in SNPs were in In are of the genetic variability within SREBF1 for ACLY, and eight for SNPs within SREBF1, ACLY, and ACACA from from from from in a and by for (SREBF1) for and (SREBF1) and for sex (P= P= and P= respectively). of (SREBF1) were of the A greater of were for (SREBF1) and for for Genotype frequencies according to the plasma TG response group to only for rs8071753 (ACLY) (P= and were observed for within ACACA gene and of according to plasma TG response from 50 from in a The rs1714987 associated with plasma TG concentrations (P= for and of the to have plasma TG concentrations mmol/l with in two SNPs (ACLY) and rs1714987 were associated with the relative change in plasma TG concentrations for and associated and within To examine the effects of these on and were to A of rs8071753 to decrease a with of rs1714987 a with of these were by to rs8071753 and rs1714987 were to be in any transcription factor or is that these SNPs be responsible for events or have a of SNPs on plasma TG response after intake of fish in of the are for and in were considered are of the are for and in were considered in a are In an to the the most associated with the relative change in plasma TG a with and the was Only the rs8071753 P= and rs1714987 P= to the In the two SNPs 7.73% of the variance in the relative change of plasma TG and were to the indicating that they were associated with the relative change in plasma TG concentrations following the n-3 PUFA supplementation. The plasma TG relative change of individuals with or for rs8071753 and for associated with a plasma TG response was with a of for the individuals with or one genotype (P= to the present certain SNPs within genes involved in de novo lipogenesis may explain of the observed in plasma TG concentrations following n-3 PUFA supplementation. The impact of n-3 PUFA on plasma TG concentrations may be by SNPs within genes involved in the de novo lipogenesis SNPs may to an increase or a decrease in the activity of the or to the to certain transcription factors the fatty acid metabolic In this two SNPs and within genes involved in de novo lipogenesis were associated with the plasma TG response following n-3 PUFA supplementation. pathway for only to the for the of healthy individuals E. F. S. in and hepatic lipid in obese and with fatty 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). However, individuals with fatty disease or with may contribute to the fatty acids for E. F. S. in and hepatic lipid in obese and with fatty 2008; Full Text Full Text PDF PubMed Scopus Google Scholar, F. P. M. of hepatic de novo lipogenesis and of plasma fatty acids to plasma triglyceride synthesis during fatty Metab. PubMed Scopus Google Scholar, A. W. pathway to from plasma and de novo lipogenesis in Res. Full Text Full Text PDF PubMed Scopus Google Scholar). is that individuals with a metabolic SNPs within genes to de novo lipogenesis may have been strongly associated with plasma TG It has been observed that from de novo lipogenesis are the hepatic as TG fatty acids are for the synthesis of in primary of J. PubMed Scopus Google Scholar). TG then be in the cytosol by by through a to fatty acids are for the synthesis of in primary of J. PubMed Scopus Google Scholar, D. A.M. A.M. and of hepatic 2004; PubMed Scopus Google Scholar). n-3 PUFA consumption a decrease in de novo lipogenesis by SREBF1 gene (9Eberle D. Hegarty B. Bossard P. Ferre P. Foufelle F. SREBP transcription factors: master regulators of lipid homeostasis.Biochimie. 2004; 86: 839-848Crossref PubMed Scopus (1004) Google Scholar, J. Teran-Garcia M. Park J.H. Nakamura M.T. Clarke S.D. Polyunsaturated fatty acids suppress hepatic sterol regulatory element-binding protein-1 expression by accelerating transcript decay.J. Biol. Chem. 2001; 276: 9800-9807Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar, 11Tanaka N. Zhang X. Sugiyama E. Kono H. Horiuchi A. Nakajima T. Kanbe H. Tanaka E. Gonzalez F.J. Aoyama T. Eicosapentaenoic acid improves hepatic steatosis independent of PPARalpha activation through inhibition of SREBP-1 maturation in mice.Biochem. Pharmacol. 2010; 80: 1601-1612Crossref PubMed Scopus (61) Google Scholar, polyunsaturated fatty acid of hepatic gene 2008; PubMed Scopus Google Scholar). In the two SNPs within SREBF1 gene and have been associated with a increase of type 2 diabetes body or and plasma TG concentrations (14Eberle D. Clement K. Meyre D. Sahbatou M. Vaxillaire M. Le G.A. Ferre P. Basdevant A. Froguel P. Foufelle F. SREBF-1 gene polymorphisms are associated with obesity and type 2 diabetes in French obese and diabetic cohorts.Diabetes. 2004; 53: 2153-2157Crossref PubMed Scopus (98) Google Scholar, 16Grarup N. Stender-Petersen K.L. Andersson E.A. Jorgensen T. Borch-Johnsen K. Sandbaek A. Lauritzen T. Schmitz O. Hansen T. Pedersen O. Association of variants in the sterol regulatory element-binding factor 1 (SREBF1) gene with type 2 diabetes, glycemia, and insulin resistance: a study of 15,734 Danish subjects.Diabetes. 2008; 57: 1136-1142Crossref PubMed Scopus (43) Google Scholar, M. I. J. G. A. L. A. et variants in sterol regulatory in of severe insulin and type 2 2004; 53: PubMed Scopus Google Scholar, J. X.D. Zhang J.P. J. Association of sterol regulatory element-binding gene polymorphism with type 2 diabetes insulin and lipid levels in Chinese Res. Clin. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). SREBF1 regulates the activity of ACLY and ACACA ACLY gene for the enzyme citrate from the to acetyl-CoA that the first of de novo The enzyme ACACA then from acetyl-CoA (12Chypre M. Zaidi N. Smans K. ATP-citrate lyase: a mini-review.Biochem. Biophys. Res. Commun. 2012; 422: 1-4Crossref PubMed Scopus (148) Google Scholar, S.J. Stoops J.K. Joshi V.C. Fatty acid synthesis and its regulation.Annu. Rev. Biochem. 1983; 52: 537-579Crossref PubMed Google Scholar). We that SNPs within these genes may the of sterol regulatory element-binding 1 with the sterol regulatory within the or M. J.H. G. gene expression and lipid in fatty induced by in Pharmacol. PubMed Scopus Google Scholar). study is the first to an association between rs8071753 within ACLY gene and plasma TG response following n-3 PUFA supplementation. is within an of ACLY gene and seem to have any regulatory impact on ACLY gene 2012. Accessed December 2012. Scholar). In ACACA the rs1714987 was associated with the plasma TG of the to have plasma TG and plasma TG concentrations by as as following n-3 PUFA supplementation. rs1714987 to have a impact on the plasma TG response following the intake of n-3 et al. (17Diaz F.J. Meary A. Arranz M.J. Ruano G. Windemuth A. de. Leon J. Acetyl-coenzyme A carboxylase alpha gene variations may be associated with the direct effects of some antipsychotics on triglyceride levels.Schizophr. Res. 2009; 115: 136-140Crossref PubMed Scopus (13) Google Scholar), have observed associations between SNPs within ACACA gene (rs1266175 and rs2229416) and plasma TG concentrations following the intake of certain antipsychotic drugs that increase the risk of these drugs have the of n-3 PUFA on lipid by lipogenesis and fatty acid Leon J. J.C. Ruano G. Windemuth A. Arranz M.J. F.J. genetic variations that may be associated with the direct effects of some antipsychotics on lipid levels.Schizophr. Res. 2008; PubMed Scopus Google Scholar, D. do fatty acids serum PubMed Scopus Google Scholar). the two SNPs associated with the relative change in plasma TG concentrations were that individuals have plasma TG concentration the intake of fish It is that individuals who different of SNPs may be an increased risk of no change or an increase of plasma TG concentrations following n-3 PUFA supplementation. However, these to be and SNPs are in to a leading to a of individuals who have a plasma TG response following n-3 PUFA supplementation. In this plasma TG concentrations were within is that with have been individuals considered as following the intake of fish this study that SNPs within genes involved in de novo lipogenesis may have an impact on the plasma TG response following the intake of fish These SNPs may gene by or are in with SNPs within genes involved in de novo lipogenesis and in metabolic such as fatty acid should be studied to the genetic the observed variability in plasma TG response after fish oil consumption. The of SNPs associated with the plasma TG response after the intake of fish oil could in the to fish oil have been without the of the participants. The and and the and for in the of participants, study and acetyl-CoA carboxylase alpha ATP citrate lyase body mass index coronary heart disease cardiovascular disease docosahexaenoic acid eicosapentaenoic acid frequency National for Nutrition transcription factor 1 single-nucleotide polymorphism sterol regulatory sterol regulatory element-binding transcription factor 1 triglyceride

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