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

6 desaturase (D6D), the rate-limiting enzyme for highly unsaturated fatty acid (HUFA) synthesis, is induced by essential fatty acid-deficient diets. Sterol regulatory elementbinding 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 aciddeficient diets. D6D mRNA induction by essential fatty aciddeficient 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. —Li, Y., T. Y. Nara, and M. T. Nakamura. Peroxisome proliferator-activated receptor is required for feedback regulation of highly unsaturated fatty acid synthesis. J. Lipid Res. 2005. 46: 2432–2440. 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 In mammals, highly unsaturated fatty acids (HUFAs) such as arachidonic acid (20:4 n-6) and docosahexaenoic acid (22:6 n-3) are present in membrane phospholipids and are required for many physiological functions, including eicosanoid signaling, skin and hair integrity, vision and brain functions, cardioprotection, and the regulation of gene expression (1). Tissue HUFAs are maintained in a narrow concentration range to perform these functions. Although mammals are unable to synthesize HUFAs from acetyl-CoA, they are capable of synthesizing HUFAs from precursor PUFA, linoleic (18:2 n-6) and -linolenic (18:3 n-3) acids (1). 6 desaturase (D6D) catalyzes the first and rate-limiting reaction of HUFA synthesis (2) and thus is subject to regulation by dietary fatty acids. D6D is induced when animals are fed a diet devoid of all n-6 and n-3 fatty acids (an essential fat-deficient diet), whereas D6D is suppressed by diets containing either a substrate or a product, the latter exerting stronger suppression (3, 4). The underlying mechanism of this D6D regulation began emerging only recently. The enzyme activity of D6D largely parallels the expression of mRNA (4), which is regulated mainly at the transcriptional level (5). Two transcription factors, sterol regulatory element-binding protein-1c (SREBP-1c) and peroxisome proliferator-activated receptor (PPAR ), are involved in the regulation of the D6D gene. SREBP-1c, a transcription factor of the basic-helixloop-helix-leucine-zipper family, induces a set of genes for fatty acid and glycerolipid synthesis (6), including all three mammalian desaturases: stearoyl-CoA desaturase (SCD) for monounsaturated fatty acid synthesis (7, 8) and D6D and 5 desaturase (D5D) for HUFA synthesis (9, 10). SREBP-1c Abbreviations: ACBP, acyl-coenzyme A binding protein; AOX, acylcoenzyme 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. 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. 2 To whom correspondence should be addressed. e-mail: [email protected] Manuscript received 9 June 2005 and in revised form 29 July 2005 and in rerevised form 4 August 2005. Published, JLR Papers in Press, August 16, 2005. DOI 10.1194/jlr.M500237-JLR200 by gest, on A uust 8, 2017 w w w .j.org D ow nladed fom