title: Absence of spontaneous peroxisome proliferation in enoyl-CoA Hydratase/L-3-hydroxyacyl-CoA dehydrogenase-deficient mouse liver. Further support for the role of fatty acyl CoA oxidase in PPARalpha ligand metabolism.
abstract: Peroxisomes contain a classical L-hydroxy-specific peroxisome proliferator-inducible beta-oxidation system and also a second noninducible D-hydroxy-specific beta-oxidation system. We previously generated mice lacking fatty acyl-CoA oxidase (AOX), the first enzyme of the L-hydroxy-specific classical beta-oxidation system; these AOX-/- mice exhibited sustained activation of peroxisome proliferator-activated receptor alpha (PPARalpha), resulting in profound spontaneous peroxisome proliferation in liver cells. These observations implied that AOX is responsible for the metabolic degradation of PPARalpha ligands. In this study, the function of enoyl-CoA hydratase/L-3-hydroxyacyl-CoA dehydrogenase (L-PBE), the second enzyme of this peroxisomal beta-oxidation system, was investigated by disrupting its gene. Mutant mice (L-PBE-/-) were viable and fertile and exhibited no detectable gross phenotypic defects. L-PBE-/- mice showed no hepatic steatosis and manifested no spontaneous peroxisome proliferation, unlike that encountered in livers of mice deficient in AOX. These results indicate that disruption of classical peroxisomal fatty acid beta-oxidation system distal to AOX step does not interfere with the inactivation of endogenous ligands of PPARalpha, further confirming that the AOX gene is indispensable for the physiological regulation of this receptor. The absence of appreciable changes in lipid metabolism also indicates that enoyl-CoAs, generated in the classical system in L-PBE-/- mice are diverted to D-hydroxy-specific system for metabolism by D-PBE. When challenged with a peroxisome proliferator, L-PBE-/- mice showed increases in the levels of hepatic mRNAs and proteins that are regulated by PPARalpha except for appreciable blunting of peroxisome proliferative response as compared with that observed in hepatocytes of wild type mice similarly treated. This blunting of peroxisome proliferative response is attributed to the absence of L-PBE protein in L-PBE-/- mouse liver, because all other proteins are induced essentially to the same extent in both wild type and L-PBE-/- mice.
authors.affiliation: Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611-3008, USA.
authors.forename: C
authors.initials: C
authors.lastname: Qi
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.forename: J
authors.initials: J
authors.lastname: Pan
authors.forename: N
authors.initials: N
authors.lastname: Usuda
authors.forename: N
authors.initials: N
authors.lastname: Maeda
authors.forename: A V
authors.initials: AV
authors.lastname: Yeldandi
authors.forename: M S
authors.initials: MS
authors.lastname: Rao
authors.forename: T
authors.initials: T
authors.lastname: Hashimoto
authors.forename: J K
authors.initials: JK
authors.lastname: Reddy
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000235:genetics*; D042962:Acyl-CoA Oxidase; D000818:Animals; D002374:Catalase / Q000378:metabolism; D002995:Clofibric Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004746:Enoyl-CoA Hydratase / Q000235:genetics*; D005227:Fatty Acids / Q000378:metabolism; D058607:Fibric Acids; D007535:Isomerases / Q000235:genetics*; D008099:Liver / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D008830:Microbodies / Q000235:genetics / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000235:genetics*; D010088:Oxidoreductases / Q000378:metabolism; D063994:Peroxisomal Bifunctional Enzyme; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D058607:Fibric Acids; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D002995:Clofibric Acid; D010088:Oxidoreductases; D015094:3-Hydroxyacyl CoA Dehydrogenases; D002374:Catalase; D042962:Acyl-CoA Oxidase; C576254:Ehhadh protein, mouse; D004746:Enoyl-CoA Hydratase; D063994:Peroxisomal Bifunctional Enzyme; D007535:Isomerases; C019304:ciprofibrate