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Biochemistry and molecular biology
The cytosolic acyl-CoA thioesterase I (Acot1) is an enzyme that hydrolyzes longchain acyl-CoAs of C12-C20-CoA in chain-length, to the free fatty acid and coenzyme A. Acot1 was previously shown to be strongly upregulated at mRNA and protein level in rodents by fibrates. In this study, we show that Acot1 mRNA levels were increased 90-fold in liver by treatment with Wy-14,643 and that Acot1 mRNA is also increased 15-fold in the liver of hepatocyte nuclear factor 4 alpha (HNF4a) knockout animals. Our study identified a direct repeat 1 (DR1) located in the Acot1 gene promotor in mouse, which binds the peroxisome proliferator-activated receptor alpha (PPARa) and the HNF4a. Chromatin immunoprecipitation assay (ChIP) showed that the identified DR1 bound PPARa/retinoid X receptor alpha (RXRa) and HNF4a, whereas the binding in ChIP was abrogated in the PPARa and HNF4a knockout mouse models. Reporter gene assays showed activation of the Acot1 promotor in cells by the PPARa agonist Wy-14,643, following co-transfection with PPARa/RXRa. However, transfection with a plasmid containing HNF4a also resulted in an increase in promotor activity. Taken together, these data show that Acot1 is under regulation by an interplay between of HNF4a and PPARa.
Dongol,B., Shah, Y., Kim, I., Gonzalez, F., Hunt, M.:The acyl-CoA thioesterase I (Acot1) is regulated by the peroxisome proliferator-activated receptor alpha and hepatocyte nuclear factor 4 alpha via a distal response element in the promotor.J. Lipid Res. 2007 48:(8) pp.1781-1791