Altered Constitutive Expression of Fatty Acid-metabolizing Enzymes in Mice Lacking the Peroxisome Proliferator-activated Receptor α (PPARα)

doi:10.1074/jbc.273.10.5678

Altered Constitutive Expression of Fatty Acid-metabolizing Enzymes in Mice Lacking the Peroxisome Proliferator-activated Receptor α (PPARα)*

From the ^‡Department of Biochemistry, Shinshu University School of Medicine, Matsumoto, Nagano 390, Japan,^¶Laboratory of Metabolism, NCI, National Institutes of Health, Bethesda Maryland 20892, ^‖Tezukayama Gakuin College, Sakai, Osaka 590, Japan, ^**Department of Hygiene and Medical Genetics, Shinshu University School of Medicine, Matsumoto, Nagano 390, Japan, and ^‡Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Nagano 390, Japan

Abstract

Peroxisome proliferator-activated receptor α (PPARα) is a member of the steroid/nuclear receptor superfamily and mediates the biological and toxicological effects of peroxisome proliferators. To determine the physiological role of PPARα in fatty acid metabolism, levels of peroxisomal and mitochondrial fatty acid metabolizing enzymes were determined in the PPARα null mouse. Constitutive liver β-oxidation of the long chain fatty acid, palmitic acid, was lower in the PPARα null mice as compared with wild type mice, indicating defective mitochondrial fatty acid catabolism. In contrast, constitutive oxidation of the very long chain fatty acid, lignoceric acid, was not different between wild type and PPARα null mice, suggesting that constitutive expression of enzymes involved in peroxisomal β-oxidation is independent of PPARα. Indeed, the PPARα null mice had normal levels of the peroxisomal acyl-CoA oxidase, bifunctional protein (hydratase + 3-hydroxyacyl-CoA dehydrogenase), and thiolase but lower constitutive expression of the D-type bifunctional protein (hydratase + 3-hydroxyacyl-CoA dehydrogenase). Several mitochondrial fatty acid metabolizing enzymes including very long chain acyl-CoA dehydrogenase, long chain acyl-CoA dehydrogenase, short chain-specific 3-ketoacyl-CoA thiolase, and long chain acyl-CoA synthetase are also expressed at lower levels in the untreated PPARα null mice, whereas other fatty acid metabolizing enzymes were not different between the untreated null mice and wild type mice. A lower constitutive expression of mRNAs encoding these enzymes was also found, suggesting that the effect was due to altered gene expression. In wild type mice, both peroxisomal and mitochondrial enzymes were induced by the peroxisome proliferator Wy-14,643; induction was not observed in the PPARα null animals. These data indicate that PPARα modulates constitutive expression of genes encoding several mitochondrial fatty acid-catabolizing enzymes in addition to mediating inducible mitochondrial and peroxisomal fatty acid β-oxidation, thus establishing a role for the receptor in fatty acid homeostasis.

Footnotes

↵* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵§ Dept. of Biochemistry, Shinshu University School of Medicine, Asahi, Matsumoto, Nagano, Japan 390. Tel.: 81-263-37-2602; Fax: 81-263-37-2604; E-mail: toshifu{at}gipac.shinshu-u.ac.jp.
↵1 The abbreviations used are: PPAR, peroxisome proliferator-activated receptor; VLCAD, very long chain acyl-CoA dehydrogenase; LCAD, long chain acyl-CoA dehydrogenase; MCAD, medium chain acyl-CoA dehydrogenase; SCAD, short chain acyl-CoA dehydrogenase; TPα, trifunctional protein α subunit (long chain- specific hydratase + long chain-specific 3-hydroxyacyl-CoA dehydrogenase); TPβ, trifunctional protein β subunit (long chain- specific 3-ketoacyl-CoA thiolase); MH, mitochondrial (short chain-specific) hydratase; SCHAD, short chain 3-hydroxyacyl-CoA dehydrogenase; T1, short chain-specific 3-ketoacyl-CoA thiolase; T2, acetoacetyl-CoA thiolase; LACS, long chain acyl-CoA synthetase; CPT II, carnitine palmitoyl-CoA transferase; MTE I, mitochondrial thioesterase I; CTE II, cytosolic thioesterase II; AOX, acyl-CoA oxidase; PH, peroxisomal bifunctional protein (hydratase + 3-hydroxyacyl-CoA dehydrogenase); DBF, D-type (peroxisomal) bifunctional protein (hydratase + 3-hydroxyacyl-CoA dehydrogenase) and key enzyme of bile acid synthesis from cholesterol; PT, peroxisomal thiolase; VLACS, very long chain acyl-CoA synthetase; ME, malic enzyme; POCA, sodium 2-[5-(4-chlorophenyl)pentyl]-oxirane-2-carboxylate.
- Received October 22, 1997.
The American Society for Biochemistry and Molecular Biology, Inc.