Omega-3 long chain fatty acid synthesis is regulated more by substrate levels than gene expression

Abstract 

The conversion of linoleic acid (LA) and alpha-linolenic acid (ALA) to long chain polyunsaturated fatty acids (LCPUFA) is known to involve desaturation and elongation steps. Although there is evidence that genes for these steps can be regulated by extremes of dietary PUFA, the degree to which there is meaningful regulation of LCPUFA levels in tissues by diet as a result of changes in expression of desaturase and elongase genes is unclear. In this study, we tested the effect of increasing ALA levels in diets of rats from 0.2% to 2.9% energy (en) against a constant LA level (1%en) on plasma and liver phospholipid LCPUFA content together with the expression of hepatic genes involved in PUFA metabolism, the desaturases FADS1 and FADS2, the elongases ELOV2 and ELOV5, and the transcription factors sterol regulatory element-binding protein-1c (SREBP-1c) and peroxisome proliferator-activated receptor alpha (PPARα). The levels of plasma and liver eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA) increased in proportion to dietary ALA whereas docosahexaenoic acid (DHA) increased only up to 1%en ALA. A low PUFA (0.4%en) reference diet stimulated the expression of delta 6 desaturase (FADS2) and elongase 2 (ELOVL2) when compared to higher PUFA diets. There was, however, no difference in the expression of any of the genes in rats, which were fed diets containing between 0.2%en and 2.9%en ALA and mRNA expression was unrelated to tissue/plasma LCPUFA content. These data suggest that the endogenous synthesis of n−3 LCPUFA from the precursor ALA is regulated independently of changes in the expression of the synthetic enzymes or regulatory transcription factor, and provides evidence that n−3 LCPUFA synthesis is regulated more by substrate competition for existing enzymes than by an increase in their mRNA expression.

Keywords: ALA, LA, DHA, Dietary PUFA level, LCPUFA biosynthesis, Gene expression, Desaturase gene, Elongase gene, ALA%en

Abbreviations: ALA, alpha-linolenic acid, DHA, docosahexaenoic acid, DPA, docosapentaenoic acid, D5D, delta 5 desaturase, D6D, delta 6 desaturase, FADS1, fatty acyl desaturase 1 gene, FADS2, fatty acyl desaturase 2 gene, EPA, eicosapentaenoic acid, ELOVL, elongation of very long chain fatty acids gene, LA, linoleic acid, LC, long chain, n-3, omega-3 fatty acids, PPARα, peroxisome proliferator-activated receptor-alpha, PUFA, polyunsaturated fatty acid, qRT-PCR, quantitative reverse transcription polymerase chain reaction, SREBP-1c, sterol regulatory element-binding protein-1c, %en, percent of energy