👤 Vincent Giguère

Tissue concentrations of fatty acids (FAs) and genetic variations are well-known factors which affect the cardiovascular disease (CVD) risk. The objective was to examine whether the genetic variability of 20 candidate genes and red blood cells (RBCs) percentage of total n-3 polyunsaturated fatty acids (PUFA), a biomarker of dietary n-3 PUFA intake, modulate lipid related CVD risk factors in the Inuit population. Data from the Qanuippitaa Nunavik Health Survey (n = 553) were analysed via multivariate regression models with 40 known polymorphisms, RBCs percentage of n-3 PUFA, and the interaction term to take into account the effect on plasma lipid and apolipoporotein levels. Individuals being heterozygotes for CETP C-4502T (rs183130) or G-971A (rs4783961) together with higher n-3 PUFA had lower triacylglycerol (TG) concentrations compared to homozygotes for the minor allele. Further, effects of a stronger beneficial association between n-3 PUFA in RBCs and plasma lipid parameters- including lower total cholesterol (TC), lower low-density lipoprotein cholesterol (LDL-C) or higher high-density lipoprotein cholesterol (HDL-C) concentrations- were associated with AGT M235T (rs699) TT genotype, CETP G-971A (rs4783961) AG genotype, T allele carriers of CETP C-4502T (rs183130), and T allele carriers of CETP Ile405Val (rs5882). In contrast, higher n-3 PUFA in RBCs were associated with adverse lipid profiles- including increased LDL-C, increased apolipoprotein B100 or decreased HDL-C concentrations- in G allele carriers of the APOA5 -3 A/G (rs651821), C allele carriers of APOA5 T-1131C (rs662799), G carriers of APOC3 SstI (rs5128) and G carriers of APOA4 Asn147Ser (rs5104). Overall, these results suggest that percentage of total n-3 PUFA of RBCs are associated with lipids related CVD risk factors conferred by genetic variations in the Inuit population. Show less

The estrogen-related receptor alpha (ERRalpha) is an orphan member of the superfamily of nuclear receptors involved in the control of energy metabolism. In particular, ERRalpha induces a high energy expenditure in the presence of the coactivator PGC-1alpha. However, ERRalpha knockout mice have reduced fat mass and are resistant to diet-induced obesity. ERRalpha is expressed in epithelial cells of the small intestine, and because the intestine is the first step in the energy chain, we investigated whether ERRalpha plays a function in dietary energy handling. Gene expression profiling in the intestine identified a subset of genes involved in oxidative phosphorylation that were down-regulated in the absence of ERRalpha. In support of the physiological role of ERRalpha in this pathway, isolated enterocytes from ERRalpha knockout mice display lower capacity for beta-oxidation. Microarray results also show altered expression of genes involved in dietary lipid digestion and absorption, such as pancreatic lipase-related protein 2 (PLRP2), fatty acid-binding protein 1 and 2 (L-FABP and I-FABP), and apolipoprotein A-IV (apoA-IV). In agreement, we found that ERRalpha-/- pups exhibit significant lipid malabsorption. We further show that the apoA-IV promoter is a direct target of ERRalpha and that its presence is required to maintain basal level but not feeding-induced regulation of the apoA-IV gene in mice. ERRalpha, in cooperation with PGC-1alpha, activates the apoA-IV promoter via interaction with the apoC-III enhancer in both human and mouse. Our results demonstrate that apoA-IV is a direct ERRalpha target gene and suggest a function for ERRalpha in intestinal fat transport, a crucial step in energy balance. Show less