Dietary long-chain polyunsaturated fatty acids upregulate expression of FADS3 transcripts

Abstract The fatty acid desaturase (FADS) gene family at 11q12-13.1 includes FADS 1 and FADS 2, both known to mediate biosynthesis of omega-3 and omega-6 long-chain polyunsaturated fatty acids (LCPUFA). FADS 3 is a putative desaturase due to its sequence similarity with FADS 1 and FADS 2, but its function is unknown. We have previously described 7 FADS 3 alternative transcripts ( AT ) and 1 FADS 2 AT conserved across multiple species. This study examined the effect of dietary LCPUFA levels on liver FADS gene expression in vivo and in vitro , evaluated by qRT-PCR. Fourteen baboon neonates were randomized to three diet groups for their first 12 weeks of life, C: Control, no LCPUFA, L: 0.33% docosahexaenoic acid (DHA)/0.67% arachidonic acid (ARA) (w/w); and L3: 1.00% DHA/0.67% ARA (w/w). Liver FADS 1 and both FADS 2 transcripts were downregulated by at least 50% in the L3 group compared to controls. In contrast, FADS 3 AT were upregulated (L3>C), with four transcripts significantly upregulated by 40% or more. However, there was no evidence for a shift in liver fatty acids to coincide with increased FADS 3 expression. Significant upregulation of FADS 3 AT was also observed in human liver-derived HepG2 cells after DHA or ARA treatment. The PPAR γ antagonist GW9662 prevented FADS 3 upregulation, while downregulation of FADS 1 and FADS 2 was unaffected. Thus, FADS 3 AT were directly upregulated by LCPUFA by a PPAR γ -dependent mechanism unrelated to regulation of other desaturases. This opposing pattern and mechanism of regulation suggests a dissimilar function for FADS 3 AT compared to other FADS gene products.