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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1235.)
© 2009 American Heart Association, Inc.

Clinical and Population Studies

Control of ACAT2 Liver Expression by HNF4

Lesson From MODY1 Patients

C. Pramfalk; E. Karlsson; L. Groop; L.L. Rudel; B. Angelin; M. Eriksson; P. Parini

From the Division of Clinical Chemistry, Department of Laboratory Medicine (C.P., P.P.), the Molecular Nutrition Unit, Department of Biosciences and Nutrition, Centre for Nutrition and Toxicology, NOVUM (C.P., B.A., M.E., P.P.), and the Metabolism Unit, Department of Medicine (C.P., B.A., M.E.), Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden; the Department of Clinical Sciences, Diabetes and Endocrinology (E.K., L.G.), Malmö University Hospital, Sweden; and the Department of Pathology (L.L.R.), Wake Forest University School of Medicine, Winston-Salem, NC.

Correspondence to Paolo Parini, MD, PhD, Division of Clinical Chemistry, Department of Laboratory Medicine, C1-74, Karolinska Institutet at Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden. E-mail paolo.parini{at}ki.se

Objective— ACAT2 is thought to be responsible for cholesteryl ester production in chylomicron and VLDL assembly. Recently, we identified HNF1 as an important regulator of the human ACAT2 promoter. Thus, we hypothesized that MODY3 (HNF1 gene mutations) and possibly MODY1 (HNF4, upstream regulator of HNF1, gene mutations) subjects may have lower VLDL esterified cholesterol.

Methods and Results— Serum analysis and lipoprotein separation using size-exclusion chromatography were performed in controls and MODY1 and MODY3 subjects. In vitro analyses included mutagenesis and cotransfections in HuH7 cells. Finally, the relevance in vivo of these findings was tested by ChIP assays in human liver. Whereas patients with MODY3 had normal lipoprotein composition, those with MODY1 had lower levels of VLDL and LDL esterified cholesterol, as well as of VLDL triglyceride. Mutagenesis revealed one important HNF4 binding site in the human ACAT2 promoter. ChIP assays and protein-to-protein interaction studies showed that HNF4, directly or indirectly (via HNF1), can bind to the ACAT2 promoter.

Conclusions— We identified HNF4 as an important regulator of the hepatocyte-specific expression of the human ACAT2 promoter. Our results suggest that the lower levels of esterified cholesterol in VLDL- and LDL-particles in patients with MODY1 may—at least in part—be attributable to lower ACAT2 activity in these patients.

HNF1 is an important regulator of human ACAT2. MODY3 and MODY1 subjects may thus have lower VLDL esterified cholesterol, which, however, was only seen in MODY1 subjects. In vitro and in vivo experiments identified HNF4 as an important regulator of the hepatocyte-specific expression of the human ACAT2 promoter.

Key Words: ACAT2 • MODY • HNF1 • HNF4 • VLDL