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Originally published In Press as doi:10.1194/jlr.M400450-JLR200 on June 16, 2005

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Journal of Lipid Research, Vol. 46, 1868-1876, September 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Control of ACAT2 liver expression by HNF1

Camilla Pramfalk*, Matthew A. Davis{dagger}, Mats Eriksson*, Lawrence L. Rudel{dagger} and Paolo Parini1,*

* Metabolism Unit, Center for Metabolism and Endocrinology, Department of Medicine and Molecular Nutrition Unit, Center for Nutrition and Toxicology, NOVUM, Karolinska Institutet at Karolinska University Hospital in Huddinge, S-141 86 Stockholm, Sweden
{dagger} Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157

Published, JLR Papers in Press, June 16, 2005. DOI 10.1194/jlr.M400450-JLR200

1 To whom correspondence should be addressed. e-mail: paolo.parini{at}cnt.ki.se

in re-

ACAT catalyzes the formation of cholesteryl esters from cholesterol and long-chain fatty acids. There are two known genes encoding the two ACAT enzymes, ACAT1 and ACAT2 (also known as Soat1 and Soat2). In adult humans, ACAT1 is present in most tissues, whereas ACAT2 is localized to enterocytes and hepatocytes. In this report, we elucidate the mechanisms that control the liver-specific expression of the human ACAT2 gene. We identified hepatic nuclear factor 1 (HNF1) as an important liver-specific trans-acting element for the human ACAT2 gene using the human hepatocellular carcinoma cell lines HuH7 and HepG2. Targeted deletion of the HNF1 binding site in the DNA sequence abolished not only the basal promoter function in HepG2 and HuH7 cells but also the induction of the ACAT2 promoter by HNF1. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that the transcription factors HNF1{alpha} and HNF1ß interact with this region in the human ACAT2 gene in vitro and in vivo.

These data indicate that a) the identified HNF1 binding site serves as a positive regulator sequence, b) the binding site is functionally active both in vivo and in vitro, and c) the transcription factors HNF1{alpha} and HNF1ß, which bind to this site, play an important part in the regulation of the human ACAT2 promoter.

Abbreviations: Cdx-2, caudal-related homeodomain protein-2; C/EBP, CCAAT/enhancer binding protein; ChIP, chromatin immunoprecipitation assay; EMSA, electrophoretic mobility shift assay; HNF1, hepatic nuclear factor 1; MODY, maturity-onset diabetes of the young; TESS, transcription element search software

Supplementary key words liver • cholesterol • transcription factor • gene regulation • metabolism • acyl-coenzyme A:cholesterol acyltransferase • hepatic nuclear factor 1


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