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 PPARα LIGAND METABOLISM

Chao Qi,Yijun Zhu,Jie Pan,Nobuteru Usuda,Nobuyo Maeda,Anjana V Yeldandi,M Sambasiva Rao,Takashi Hashimoto,Janardan K Reddy

doi:10.1074/jbc.274.22.15775

Chao Qi, Yijun Zhu + Show 7 more

Open Access

https://doi.org/10.1074/jbc.274.22.15775

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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.

Highlights

Peroxisomes contain a classical L-hydroxy-specific peroxisome proliferator-inducible ␤-oxidation system and a second noninducible D-hydroxy-specific ␤-oxidation system
We describe the generation of mice homozygous for a disruption of the L-PBE gene, which encodes the second enzyme of this ␤-oxidation spiral and report that these mice do not exhibit phenotypic alterations such as those found in acyl-CoA oxidase (AOX) null mice, further confirming that disruption of this classical ␤-oxidation pathway distal to AOX does not affect the metabolism of natural ligands of PPAR␣
The classical peroxisome proliferator-inducible L-hydroxyspecific peroxisomal ␤-oxidation system that acts on long and very long straight chain acyl-CoAs, long chain dicarboxylylCoAs, and the CoA esters of prostaglandins consists of AOX, L-PBE, and PTL [2, 3]

Summary

Introduction

Peroxisomes contain a classical L-hydroxy-specific peroxisome proliferator-inducible ␤-oxidation system and a second noninducible D-hydroxy-specific ␤-oxidation system. We previously generated mice lacking fatty acyl-CoA oxidase (AOX), the first enzyme of the L-hydroxy-specific classical ␤-oxidation system; these AOX؊/؊ mice exhibited sustained activation of peroxisome proliferator-activated receptor ␣ (PPAR␣), resulting in profound spontaneous peroxisome proliferation in liver cells. To investigate the functional implications of PPAR␣-regulated L-hydroxy-specific ␤-oxidation system, we recently generated mice deficient in AOX, the first enzyme of this inducible system, and found that they exhibit steatohepatitis and spontaneous peroxisome proliferation in liver cells [10] These results suggested that straight chain acyl-CoAs and other putative substrates for classical AOX serve as natural ligands for PPAR␣, and this enzyme is indispensable for the physiological regulation of PPAR␣ [10]. We describe the generation of mice homozygous for a disruption of the L-PBE gene, which encodes the second enzyme of this ␤-oxidation spiral and report that these mice do not exhibit phenotypic alterations such as those found in AOX null mice, further confirming that disruption of this classical ␤-oxidation pathway distal to AOX does not affect the metabolism of natural ligands of PPAR␣

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