Gene-nutrient interactions with dietary fat modulate the association between genetic variation of the ACSL1 gene and metabolic syndrome

Catherine M Phillips,Louisa Goumidi,Sandrine Bertrais,Martyn R Field,L Adrienne Cupples,Jose M Ordovas,Catherine Defoort,Julie A Lovegrove,Christian A Drevon,Michael J Gibney,Ellen E Blaak,Beata Kiec-Wilk,Britta Karlstrom,Jose Lopez-Miranda,Ross Mcmanus,Serge Hercberg,Denis Lairon,Richard Planells,Helen M Roche

doi:10.1194/jlr.m003046

Abstract

Long-chain acyl CoA synthetase 1 (ACSL1) plays an important role in fatty acid metabolism and triacylglycerol (TAG) synthesis. Disturbance of these pathways may result in dyslipidemia and insulin resistance, hallmarks of the metabolic syndrome (MetS). Dietary fat is a key environmental factor that may interact with genetic determinants of lipid metabolism to affect MetS risk. We investigated the relationship between ACSL1 polymorphisms (rs4862417, rs6552828, rs13120078, rs9997745, and rs12503643) and MetS risk and determined potential interactions with dietary fat in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n = 1,754). GG homozygotes for rs9997745 had increased MetS risk {odds ratio (OR) 1.90 [confidence interval (CI) 1.15, 3.13]; P = 0.01}, displayed elevated fasting glucose (P = 0.001) and insulin concentrations (P = 0.002) and increased insulin resistance (P = 0.03) relative to the A allele carriers. MetS risk was modulated by dietary fat, whereby the risk conferred by GG homozygosity was abolished among individuals consuming either a low-fat (<35% energy) or a high-PUFA diet (>5.5% energy). In conclusion, ACSL1 rs9997745 influences MetS risk, most likely via disturbances in fatty acid metabolism, which was modulated by dietary fat consumption, particularly PUFA intake, suggesting novel gene-nutrient interactions.

Highlights

Long-chain acyl CoA synthetase 1 (ACSL1) plays an important role in fatty acid metabolism and triacylglycerol (TAG) synthesis
Genotype frequencies were different between metabolic syndrome (MetS) cases and controls for rs9997745 (P = 0.019), whereby the major G allele was more frequent in the MetS cases in the recessive model (P = 0.0077)
We demonstrated an association between a common genetic variant at the long-chain acyl CoA synthetase 1 (ACSL1) locus with increased MetS risk

Summary

Introduction

Long-chain acyl CoA synthetase 1 (ACSL1) plays an important role in fatty acid metabolism and triacylglycerol (TAG) synthesis Disturbance of these pathways may result in dyslipidemia and insulin resistance, hallmarks of the metabolic syndrome (MetS). Prolonged dietary excess (high-fat, obesogenic, insulin-desensitizing diets) and surplus adipose tissue initiate a state of cellular stress and secretion of proinflammatory cytokines leading to increased lipolysis, decreased triacylglycerol (TAG) synthesis, and increased nonesterified fatty acids (NEFA) availability. This results in accumulation of TAG and activated lipids in the form of long-chain fatty acyl-CoA esters, which disrupt normal metabolic functions in adipocytes, muscle, and liver [3]. ACSL1 is a target of peroxisome proliferator activated receptor (PPAR)-␥, whereas in the liver, ACSL1 is a target of PPAR-␣, suggesting divergent functional roles of ACSL1 in different tissues [13, 14]

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