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J. Biol. Chem., Vol. 278, Issue 47, 47232-47239, November 21, 2003

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Overexpression of Peroxisome Proliferator-activated Receptor- (PPAR)-regulated Genes in Liver in the Absence of Peroxisome Proliferation in Mice Deficient in both L- and D-Forms of Enoyl-CoA Hydratase/Dehydrogenase Enzymes of Peroxisomal -Oxidation System^*

Yuzhi Jia, Chao Qi, Zhongyi Zhang, Takashi Hashimoto, M. Sambasiva Rao, Steven Huyghe, Yasuyuki Suzuki¶, Paul P. Van Veldhoven, Myriam Baes, and Janardan K. Reddy||

From the Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611-3008, the Laboratory of Clinical Chemistry, Faculty of Pharmaceutical Sciences, K.U. Leuven, Herestraat 490/N B3000 Leuven, Belgium, and ^¶The Department of Pediatrics, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500, Japan

Peroxisomal -oxidation system consists of peroxisome proliferator-activated receptor (PPAR)-inducible pathway capable of catalyzing straight-chain acyl-CoAs and a second noninducible pathway catalyzing the oxidation of 2-methyl-branched fatty acyl-CoAs. Disruption of the inducible -oxidation pathway in mice at the level of fatty acyl-CoA oxidase (AOX), the first and rate-limiting enzyme, results in spontaneous peroxisome proliferation and sustained activation of PPAR, leading to the development of liver tumors, whereas disruptions at the level of the second enzyme of this classical pathway or of the noninducible system had no such discernible effects. We now show that mice with complete inactivation of peroxisomal -oxidation at the level of the second enzyme, enoyl-CoA hydratase/L-3-hydroxyacyl-CoA dehydrogenase (L-PBE) of the inducible pathway and D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase (D-PBE) of the noninducible pathway (L-PBE^-/-D-PBE^-/-), exhibit severe growth retardation and postnatal mortality with none surviving beyond weaning. L-PBE^-/-D-PBE^-/- mice that survived exceptionally beyond the age of 3 weeks exhibited overexpression of PPAR-regulated genes in liver, despite the absence of morphological evidence of hepatic peroxisome proliferation. These studies establish that peroxisome proliferation in rodent liver is highly correlatable with the induction mostly of the L- and D-PBE genes. We conclude that disruption of peroxisomal fatty acid -oxidation at the level of second enzyme in mice leads to the induction of many of the PPAR target genes independently of peroxisome proliferation in hepatocytes, raising the possibility that intermediate metabolites of very long-chain fatty acids and peroxisomal -oxidation act as ligands for PPAR

Received for publication, June 16, 2003 , and in revised form, August 7, 2003.

^* This work was supported by National Institutes of Health Grants GM23750 (to J. K. R.) and CA84472 (to M. S. R.) and by Fonds Wetenschappelijk Onderzoek Vlaanderen G 0235 01, Geconcerteerde Onderzoeksacties GOA/99/-09 and European Community Grant QLG1-CT2001-01299 (to M. B. and P. V. V.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed:Dept. of pathology, Northwestern University, Feinberg School of Medicine, 303 East Chicago Ave., Chicago, IL 60611-3008. Tel.: 312-505-8144; Fax: 312-503-8249; E-mail: jkreddy{at}northwestern.edu.

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