Abstract
Delta6 desaturase (D6D), the rate-limiting enzyme for highly unsaturated fatty acid (HUFA) synthesis, is induced by essential fatty acid-deficient diets. Sterol regulatory element-binding protein-1c (SREBP-1c) in part mediates this induction. Paradoxically, D6D is also induced by ligands of peroxisome proliferator-activated receptor alpha (PPARalpha). Here, we report a novel physiological role of PPARalpha in the induction of genes specific for HUFA synthesis by essential fatty acid-deficient diets. D6D mRNA induction by essential fatty acid-deficient diets in wild-type mice was diminished in PPARalpha-null mice. This impaired D6D induction in PPARalpha-null mice was not attributable to feedback suppression by tissue HUFAs because PPARalpha-null mice had lower HUFAs in liver phospholipids than did wild-type mice. Furthermore, PPARalpha-responsive genes were induced in wild-type mice under essential fatty acid deficiency, suggesting the generation of endogenous PPARalpha ligand(s). Contrary to genes for HUFA synthesis, the induction of other lipogenic genes under essential fatty acid deficiency was higher in PPARalpha-null mice than in wild-type mice even though mature SREBP-1c protein did not differ between the genotypes. The expression of PPARgamma was markedly increased in PPARalpha-null mice and might have contributed to the induction of genes for de novo lipogenesis. Our study suggests that PPARalpha, together with SREBP-1c, senses HUFA status and confers pathway-specific induction of HUFA synthesis by essential fatty acid-deficient diets.
Highlights
Abstract ⌬6 desaturase (D6D), the rate-limiting enzyme for highly unsaturated fatty acid (HUFA) synthesis, is induced by essential fatty acid-deficient diets
D6D mRNA induction by essential fat-deficient diets was diminished in peroxisome proliferator-activated receptor (PPAR)␣-null mice
There was no significant difference in body weight between wild-type and PPAR␣-null mice
Summary
Abstract ⌬6 desaturase (D6D), the rate-limiting enzyme for highly unsaturated fatty acid (HUFA) synthesis, is induced by essential fatty acid-deficient diets. We report a novel physiological role of PPAR␣ in the induction of genes specific for HUFA synthesis by essential fatty aciddeficient diets. PPAR␣responsive genes were induced in wild-type mice under essential fatty acid deficiency, suggesting the generation of endogenous PPAR␣ ligand(s). Contrary to genes for HUFA synthesis, the induction of other lipogenic genes under essential fatty acid deficiency was higher in PPAR␣-null mice than in wild-type mice even though mature SREBP-1c protein did not differ between the genotypes. Our study suggests that PPAR␣, together with SREBP-1c, senses HUFA status and confers pathway-specific induction of HUFA synthesis by essential fatty acid-deficient diets.—Li, Y., T. Peroxisome proliferator-activated receptor ␣ is required for feedback regulation of highly unsaturated fatty acid synthesis. Sterol regulatory element-binding protein-1c (SREBP-1c) and peroxisome proliferator-activated receptor ␣ (PPAR␣), are involved in the regulation of the D6D gene.
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