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Journal of Lipid Research, Vol. 48, 1781-1791, August 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

The acyl-CoA thioesterase I is regulated by PPAR and HNF4 via a distal response element in the promoter

Bikesh Dongol^*, Yatrik Shah, Insook Kim, Frank J. Gonzalez and Mary C. Hunt^1,*

^* Karolinska Institutet, Department of Laboratory Medicine, Division of Clinical Chemistry C1-74, Karolinska University Hospital at Huddinge, S-141 86 Stockholm, Sweden
Laboratory of Metabolism, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

Published, JLR Papers in Press, May 7, 2007.

¹ To whom correspondence should be addressed. e-mail: mary.hunt{at}ki.se

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 4 (HNF4) 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 (PPAR) and HNF4. Chromatin immunoprecipitation (ChIP) assay showed that the identified DR1 bound PPAR/retinoid X receptor (RXR) and HNF4, whereas the binding in ChIP was abrogated in the PPAR and HNF4 knockout mouse models. Reporter gene assays showed activation of the Acot1 promoter in cells by the PPAR agonist Wy-14,643 after cotransfection with PPAR/RXR. However, transfection with a plasmid containing HNF4 also resulted in an increase in promoter activity. Together, these data show that Acot1 is under regulation by an interplay between HNF4 and PPAR.

Supplementary key words peroxisome proliferator response element • peroxisome proliferator-activated receptor • direct repeat 1 • acyl-coenzyme A • lipid metabolism • hepatic nuclear factor 4

Abbreviations: Acot1, acyl-coenzyme A thioesterase I; ChIP, chromatin immunoprecipitation; DR1, direct repeat 1; EMSA, electromobility shift assay; HNF4, hepatic nuclear factor 4; MCAD, medium-chain acyl-coenzyme A dehydrogenase; OTC, ornithine transcarbamylase; PPAR, peroxisome proliferator-activated receptor ; PPRE, peroxisome proliferator response element; RXR, retinoid X receptor

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