Submitted on June 9, 2005
Revised on August 4, 2005
Accepted on August 5, 2005
Peroxisome proliferator activated receptor 
is required for feedback regulation of highly unsaturated fatty acid synthesis
Yue Li, Takayuki Y. Nara, and Manabu T. Nakamura
Department of Food Science and Human Nutrition, University fo Illinois at Urbana-Champaign, Urbana, IL 61801
Corresponding Author: mtnakamu{at}uiuc.edu
Delta-6 desaturase (D6D), the rate-limiting enzyme for highly unsaturated fatty acid (HUFA) synthesis, is induced by essential fatty acid (EFA) deficient diets. Sterol regulatory element-binding protein-1c (SREBP-1c) in part mediates the induction. Paradoxically, D6D is also induced by ligands of peroxisome proliferator-activated receptor-a (PPARa). Here we report a novel physiological role of PPARa in induction of genes specific for HUFA synthesis by EFA deficient diets. D6D mRNA induction by EFA deficient diets in wild type mice (+/+) was diminished in PPARa-null mice (-/-). This impaired D6D induction in -/- was not due to feedback suppression by tissue HUFAs because -/- had lower HUFAs in liver phospholipids than +/+. Furthermore, PPARa responsive genes were induced in +/+ under EFA deficiency, suggesting generation of endogenous PPARa ligand(s). Contrary to genes for HUFA synthesis, induction of other lipogenic genes under EFA deficiency was higher in -/- than +/+ even though mature SREBP-1c protein did not differ between the genotypes. Expression of PPAR
was markedly increased in -/- and might have contributed to induction of genes for de novo lipogenesis. Our study suggests that PPARa, together with SREBP-1c, senses HUFA status and confers pathway specific induction of HUFA synthesis by EFA deficient diets.
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