The acyl-CoA thioesterase I is regulated by PPARα and HNF4α via a distal response element in the promoter

The cytosolic acyl-coenzyme A 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 CoA. Acot1 was shown previously to be strongly upregulated at the mRNA and protein level in rodents by fibrates. In this study, we show that Acot1 mRNA levels were increased by 90-fold in liver by treatment with Wy-14,643 and that Acot1 mRNA was also increased by 15-fold in the liver of hepatocyte nuclear factor 4α (HNF4α) knockout animals. Our study identified a direct repeat 1 (DR1) located in the Acot1 gene promoter in mouse, which binds the peroxisome proliferator-activated receptor α (PPARα) and HNF4α. Chromatin immunoprecipitation (ChIP) assay showed that the identified DR1 bound PPARα/retinoid X receptor α (RXRα) and HNF4α, whereas the binding in ChIP was abrogated in the PPARα and HNF4α knockout mouse models. Reporter gene assays showed activation of the Acot1 promoter in cells by the PPARα agonist Wy-14,643 after cotransfection with PPARα/RXRα. However, transfection with a plasmid containing HNF4α also resulted in an increase in promoter activity. Together, these data show that Acot1 is under regulation by an interplay between HNF4α and PPARα.