Peroxisome proliferator-activated receptor α is required for feedback regulation of highly unsaturated fatty acid synthesis

Delta 6 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 (PPAR alpha). Here, we report a novel physiological role of PPAR alpha 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 PPAR alpha-null mice. This impaired D6D induction in PPAR alpha-null mice was not attributable to feedback suppression by tissue HUFAs because PPAR alpha-null mice had lower HUFAs in liver phospholipids than did wild-type mice. Furthermore, PPAR alpha responsive genes were induced in wild-type mice under essential fatty acid deficiency, suggesting the generation of endogenous PPAR alpha ligand(s). Contrary to genes for HUFA synthesis, the induction of other lipogenic genes under essential fatty acid deficiency was higher in PPAR alpha-null mice than in wild-type mice even though mature SREBP-1c protein did not differ between the genotypes. The expression of PPAR gamma was markedly increased in PPAR alpha-null mice and might have contributed to the induction of genes for de novo lipogenesis. Our study suggests that PPAR alpha, together with SREBP-1c, senses HUFA status and confers pathway-specific induction of HUFA synthesis by essential fatty acid-deficient diets.