Abstract

Peroxisome proliferator-activated receptor alpha (PPARalpha) 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 PPARalpha in fatty acid metabolism, levels of peroxisomal and mitochondrial fatty acid metabolizing enzymes were determined in the PPARalpha null mouse. Constitutive liver beta-oxidation of the long chain fatty acid, palmitic acid, was lower in the PPARalpha 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 PPARalpha null mice, suggesting that constitutive expression of enzymes involved in peroxisomal beta-oxidation is independent of PPARalpha. Indeed, the PPARalpha 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 PPARalpha 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 PPARalpha null animals. These data indicate that PPARalpha modulates constitutive expression of genes encoding several mitochondrial fatty acid-catabolizing enzymes in addition to mediating inducible mitochondrial and peroxisomal fatty acid beta-oxidation, thus establishing a role for the receptor in fatty acid homeostasis.

Highlights

  • Peroxisome proliferator-activated receptor ␣ (PPAR␣) is a member of the steroid/nuclear receptor superfamily and mediates the biological and toxicological effects of peroxisome proliferators

  • Constitutive expression of very long chain acyl-CoA dehydrogenase (VLCAD), long chain acyl-CoA dehydrogenase (LCAD), short chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), T1, long chain acyl-CoA synthetase (LACS), D-type bifunctional protein (DBF), and malic enzyme (ME) is regulated by peroxisome proliferator-activated receptor (PPAR)␣ since their abundance was significantly altered in the absence of PPAR␣ as compared with wild type controls

  • With the exception of SCHAD, which was up-regulated in the PPAR␣ null mice, all of these proteins were found at lower levels in the PPAR␣ null mice

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Summary

THE JOURNAL OF BIOLOGICAL CHEMISTRY

5678 –5684, 1998 Printed in U.S.A. Altered Constitutive Expression of Fatty Acid-metabolizing Enzymes in Mice Lacking the Peroxisome Proliferator-activated Receptor ␣ (PPAR␣)*. Compared with wild type mice, administration of peroxisome proliferators to PPAR␣ null mice does not cause an increase in the number of peroxisomes, hepatomegaly, nor increases in mRNA encoded by target genes. These mice do not display physiological, toxicological, or carcinogenic responses induced by peroxisome proliferators [11,12,13]. The cDNA probes used were for VLCAD [35], LCAD [36], LACS [37], ME [38], and SCHAD [39]

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