Influence of genotype on the modulation of gene and protein expression by n-3 LC-PUFA in rats

Abstract

It is becoming increasingly apparent that responsiveness to dietary fat composition is heterogeneous and dependent on the genetic make-up of the individual. The aim of this study was to evidence a genotype-related differential effect of n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) on the modulation of hepatic genes involved in cholesterol metabolism. Fourteen spontaneously hypertensive (SH) rats, which present a naturally occurring variation in the gene encoding for sterol responsive element binding protein 1 (SREBP-1), contributing to their inherited variation in lipid metabolism, and 14 Wistar-Kyoto (WK) rats were fed a control diet or an n-3 LC-PUFA enriched diet for 90 days. Plasma lipid profile, total lipid fatty acid composition in plasma and liver, and the expression of SREBP-1 and 2, 3-hydroxy-3-methyl-glutaryl-CoA reductase, low-density lipoprotein receptor, and acyl-CoA:cholesterol acyltransferase 2 encoding genes and proteins were determined. The positive effect of the enriched diet on the serum lipid profile, particularly on total cholesterol and triglyceride level, was clearly evidenced in both WK and SH rats, but n-3 LC-PUFA acted through a different modulation of gene and protein expression that appeared related to the genetic background. Our study evidences a different transcriptional effect of specific nutrients related to genetic variants.

Synergic hypocholesterolaemic effect ofn-3 PUFA and oestrogen by modulation of hepatic cholesterol metabolism in female rats

“…PCSK9 has been shown to be regulated by SREBP-2, which communicates with hepatic proteins involved in cholesterol synthesis such as p-AMPK, AMPK and HMG-CoA reductase ( 23 ) . Previous preclinical studies have suggested that E 2 injection ( 4 , 24 ) or n -3 PUFA supplementation ( 11 , 25 ) reduce cholesterol synthesis by increasing AMPK phosphorylation, reducing expression of HMG-CoA reductase and reducing expression of SREBP-2 . Consistently, the present study shows that the reduced hepatic cholesterol synthesis was due to an up-regulation of p-AMPK and AMPK, an increase in the p-AMPK:AMPK ratio, and a down-regulation of HMG-CoA reductase and SREBP-2.…”

“…Unlike oestrogen, n -3 PUFA, EPA (20 : 5 n -3) and DHA (22 : 6 n -3) have been shown to decrease cholesterol by increasing hepatic bile acid synthesis by up-regulation of CYP7A1 , sterol 12 α -hydroxylase ( CYP8B1 ) and sterol 27-hydroxylase ( CYP27A1 ) ( 9 , 10 ) . In addition to increasing synthesis of bile acids, n -3 PUFA decrease blood levels of cholesterol by down-regulating SREBP-2 and HMG-CoA reductase and, thus, decreasing hepatic cholesterol synthesis ( 11 , 12 ) . However, the effect of n -3 PUFA on hepatic expression of PCSK9 has not been studied.…”

Epigenetic Effects of Human Breast Milk

“…High cholesterol intake in infancy may reduces endogenous cholesterol synthesis, probably by down-regulation of hepatic hydroxymethyl glutaryl coenzyme A (HMGCoA) reductase [ 45 , 46 ]. Additionally it has been showed that n -3 LCPUFA may modulate the HMGCoA reductase expression in rats [ 47 ]. This epigenetic mechanism, high cholesterol content in breast milk and down-regulation of HMGCoA reductase, might be further studied.…”

Estrogen and n-3 polyunsaturated fatty acid supplementation have a synergistic hypotriglyceridemic effect in ovariectomized rats

“…Previous studies consistently observed that the supplementation of n-3 PUFA containing EPA and DHA significantly reduced blood concentrations of TG, TC, and LDL cholesterol in animals (Harris and Bulchandani 2006;Boschetti et al 2013) and humans (Ras et al 2014). The present study also showed that n-3 PUFA supplementation significantly and dose-dependently reduced serum and liver levels of lipids.…”