Molecular cloning and characterization of two mouse peroxisome proliferator-activated receptor α (PPARα)-regulated peroxisomal Acyl-CoA thioesterases

Peroxisomes are organelles that function in the beta-oxidation of long- and very long- chain acyl- CoAs, bile acid- CoA intermediates, prostaglandins, leukotrienes, thromboxanes, dicarboxylic fatty acids, pristanic acid, and xenobiotic carboxylic acids. The very long- and long- chain acyl- CoAs are mainly chain- shortened and then transported to mitochondria for further metabolism. We have now identified and characterized two peroxisomal acyl- CoA thioesterases, named PTE- Ia and PTE- Ic, that hydrolyze acyl- CoAs to the free fatty acid and coenzyme A. PTE- Ia and PTE- Ic show 82% sequence identity at the amino acid level, and a putative peroxisomal type 1 targeting signal of - AKL was identified at the carboxyl- terminal end of both proteins. Localization experiments using green fluorescent fusion protein showed PTE- Ia and PTE- Ic to be localized in peroxisomes. Despite their high level of sequence identity, we show that PTE- Ia is mainly active on long- chain acyl-CoAs, whereas PTE- Ic is mainly active on medium- chain acyl- CoAs. Lack of regulation of enzyme activity by free CoASH suggests that PTE- Ia and PTE- Ic regulate intra-peroxisomal levels of acyl- CoA, and they may have a function in termination of beta- oxidation of fatty acids of different chain lengths. Tissue expression studies revealed that PTE- Ia is highly expressed in kidney, whereas PTE- Ic is most highly expressed in spleen, brain, testis, and proximal and distal intestine. Both PTE- Ia and PTE- Ic were highly up- regulated in mouse liver by treatment with the peroxisome proliferator WY- 14,643 and by fasting in a peroxisome proliferator- activated receptor alpha- dependent manner. These data show that PTE- Ia and PTE- Ic have different functions based on different substrate specificities and tissue expression.