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Journal of Lipid Research, Vol. 46, 2432-2440, November 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Peroxisome proliferator-activated receptor is required for feedback regulation of highly unsaturated fatty acid synthesis¹

Yue Li, Takayuki Y. Nara and Manabu T. Nakamura²

Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801

¹ Part of the work was presented at the Experimental Biology Conference [Li, Y., T.Y. Nara, and M.T. Nakamura. 2004. Regulation of highly unsaturated fatty acid synthesis: a new physiological role of peroxisome proliferator-activated receptor alpha (abstract). FASEB J. 18: A863] and cited in reference 1.

Published, JLR Papers in Press, August 16, 2005. DOI 10.1194/jlr.M500237-JLR200

² To whom correspondence should be addressed. e-mail: mtnakamu{at}uiuc.edu

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 (PPAR). Here, we report a novel physiological role of PPAR 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-null mice. This impaired D6D induction in PPAR-null mice was not attributable to feedback suppression by tissue HUFAs because PPAR-null mice had lower HUFAs in liver phospholipids than did wild-type mice. Furthermore, 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. The expression of PPAR was markedly increased in PPAR-null mice and might have contributed to the induction of genes for de novo lipogenesis.

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.

Abbreviations: ACBP, acyl-coenzyme A binding protein; AOX, acyl-coenzyme A oxidase; CYP, cytochrome P450; D5D, 5 desaturase; D6D, 6 desaturase; HUFA, highly unsaturated fatty acid; PK, pyruvate kinase; PPAR, peroxisome proliferator-activated receptor; PPRE, peroxisome proliferator response element; SCD, stearoyl-coenzyme A desaturase; SREBP, sterol regulatory element-binding protein; TRB3, mammalian tribbles homolog

Supplementary key words 6 desaturase • arachidonic acid • docosahexaenoic acid • essential fat deficiency • liver • peroxisome proliferator-activated receptor -null mouse • polyunsaturated fatty acid • sterol regulatory element-binding protein-1c

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