Compensatory induction of Fads1 gene expression in heterozygous Fads2-null mice and by diet with a high n-6/n-3 PUFA ratio

Hang Su,Dan Zhou,Yuan-Xiang Pan,Xingguo Wang,Manabu T Nakamura

doi:10.1194/jlr.m064956

Abstract

In mammals, because they share a single synthetic pathway, n-6/n-3 ratios of dietary PUFAs impact tissue arachidonic acid (ARA) and DHA content. Likewise, SNPs in the human fatty acid desaturase (FADS) gene cluster impact tissue ARA and DHA. Here we tested the feasibility of using heterozygous Fads2-null-mice (HET) as an animal model of human FADS polymorphisms. WT and HET mice were fed diets with linoleate/α-linolenate ratios of 1:1, 7:1, and 44:1 at 7% of diet. In WT liver, ARA and DHA in phospholipids varied >2× among dietary groups, reflecting precursor ratios. Unexpectedly, ARA content was only <10% lower in HET than in WT livers, when fed the 44:1 diet, likely due to increased Fads1 mRNA in response to reduced Fads2 mRNA in HET. Consistent with the RNA data, C20:3n-6, which is elevated in minor FADS haplotypes in humans, was lower in HET than WT. Diet and genotype had little effect on brain PUFAs even though brain Fads2 mRNA was low in HET. No differences in cytokine mRNA were found among groups under unstimulated conditions. In conclusion, differential PUFA profiles between HET mice and human FADS SNPs suggest low expression of both FADS1 and 2 genes in human minor haplotypes.

Highlights

In mammals, because they share a single synthetic pathway, n-6/n-3 ratios of dietary PUFAs impact tissue arachidonic acid (ARA) and DHA content
Difference was considered significant at P < 0.05. Both diet and genotype affected mRNA expression of desaturases and elongases in liver No significant dietary or genotype effect was observed in body weight, tissue weight, plasma lipids, or liver TG, brain was heavier in soybean oil (SO)-fed heterozygous Fads2-null-mice (HET) than in corn oil (CO)-fed WT, and plasma cholesterol was lower in SO-fed HET than in CO-fed HET by least significant difference (LSD) test
In the liver of WT, the CO group with a high ratio of dietary n-6/n-3 precursors increased the mRNA of all 4 synthetic enzymes, Fads2, Fads1, Elovl5, and Elovl2, compared with SO and flaxseed and canola oil (FCO) groups, whereas none of four genes was different between SO and FCO (Fig. 1A)

Summary

Introduction

Because they share a single synthetic pathway, n-6/n-3 ratios of dietary PUFAs impact tissue arachidonic acid (ARA) and DHA content. SNPs in the human fatty acid desaturase (FADS) gene cluster impact tissue ARA and DHA. Differential PUFA profiles between HET mice and human FADS SNPs suggest low expression of both FADS1 and 2 genes in human minor haplotypes.—Su, H., D. Compensatory induction of Fads gene expression in heterozygous Fads2-null mice and by diet with a high n-6/n-3 PUFA ratio. Minor alleles (designated by the Linoleic acid (C18:2 n-6; LA) and -linolenic acid (C18:3 n-3; ALA) are essential FAs because they cannot be synthesized in mammals and must be obtained from diet [1, 2]. They are precursors of the physiologically essential highly.

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Conclusion