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

Bikesh Dongol, Yatrik Shah, Insook Kim, Frank J. Gonzalez, and Mary C. Hunt

Department of Laboratory Medicine, Karolinska Institutet, Stockholm

Corresponding Author: mary.hunt{at}ki.se

The cytosolic acyl-CoA thioesterase I (Acot1) is an enzyme that hydrolyzes long-chain 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 (HNF4 $alpha$ ) 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 (PPAR $alpha$ ) and the HNF4 $alpha$ . Chromatin immunoprecipitation assay (ChIP) showed that the identified DR1 bound PPAR $alpha$ /retinoid X receptor alpha (RXR $alpha$ ) and HNF4 $alpha$ , whereas the binding in ChIP was abrogated in the PPAR $alpha$ and HNF4 $alpha$ knockout mouse models. Reporter gene assays showed activation of the Acot1 promotor in cells by the PPAR $alpha$ agonist Wy-14,643, following co-transfection with PPAR $alpha$ /RXR $alpha$ . However, transfection with a plasmid containing HNF4 $alpha$ also resulted in an increase in promotor activity. Taken together, these data show that Acot1 is under regulation by an interplay between of HNF4 $alpha$ and PPAR $alpha$ .

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