ALTERED CONSTITUTIVE EXPRESSION OF FATTY ACID-METABOLIZING ENZYMES INMICE LACKING THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-ALPHA (PPAR-ALPHA)

Peroxisome proliferative-activated receptor alpha (PPAR alpha) is a me mber of the steroid/nuclear receptor superfamily and mediates the biol ogical and toxicological effects of peroxisome proliferators. To deter mine the physiological role of PPAR alpha in fatty acid metabolism, le vels of peroxisomal and mitochondrial fatty acid metabolizing enzymes were determined in the PPAR alpha null mouse, Constitutive liver beta- oxidation of the long chain fatty acid, palmitic acid, was lower in th e PPAR alpha null mice as compared with wild type mice, indicating def ective mitochondrial fatty acid catabolism. In contrast, constitutive oxidation of the very long chain fatty acid, lignoceric acid, was not different between wild type and PPAR alpha null mice, suggesting that constitutive expression of enzymes involved in peroxisomal beta-oxidat ion is independent of PPAR alpha. Indeed, the PPAR alpha null mice had normal levels of the peroxisomal acyl-CoA oxidase, bifunctional prote in (hydratase + 3-hydroxyacyl-CoA dehydrogenase), and thiolase but low er constitutive expression of the D-type bifunctional protein (hydrata se + 3-hydroxyacyl-CoA dehydrogenase), Several mitochondrial fatty aci d metabolizing enzymes including very long chain acyl-CoA dehydrogenas e, 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 PPAR alpha null mice, whereas other fat ty 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 a nd mitochondrial enzymes were induced by the peroxisome proliferator W y-14,643; induction was not observed in the PPAR alpha null animals, T hese data indicate that PPAR alpha modulates constitutive expression o f genes encoding several mitochondrial fatty acid-catabolizing enzymes in addition to mediating inducible mitochondrial and peroxisomal fatt y acid beta-oxidation, thus establishing a role for the receptor in fa tty acid homeostasis.