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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2724.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Cholesterol 7-Hydroxylase Deficiency in Mice on an APOE*3-Leiden Background Increases Hepatic ABCA1 mRNA Expression and HDL-Cholesterol

Sabine M. Post; Martine Groenendijk; Caroline C. van der Hoogt; Catherine Fievet; Gérald Luc; Menno Hoekstra; Hans M.G. Princen; Bart Staels; Patrick C.N. Rensen

From TNO-Quality of Life, Department of Biomedical Research, (S.M.P., M.G., C.C.H., H.M.G.P., P.C.N.R.) Gaubius Laboratory, Leiden, The Netherlands; Département d’Athérosclérose and INSERM U545 (C.F., G.L., B.S.), Institut Pasteur de Lille and Faculté de Pharmacie, Université de Lille II, Lille, France; Leiden University Medical Center (C.C.H., P.C.N.R.), Department of General Internal Medicine, Endocrinology, and Metabolic Diseases, Leiden, The Netherlands; and Leiden/Amsterdam Center for Drug Research (M.H.), Division of Biopharmaceutics, Leiden, The Netherlands.

Correspondence to Patrick C.N. Rensen, PhD, Leiden University Medical Center, Department of Endocrinology and Metabolic Diseases, C4-R81, Albinusdreef 2, PO Box 9600, 2300 RC Leiden, The Netherlands. E-mail P.C.N.Rensen{at}lumc.nl

Objective— High-density lipoprotein (HDL) plays a key role in protection against development of atherosclerosis by reducing inflammation, protecting against LDL oxidation, and promoting reverse cholesterol transport from peripheral tissues to the liver for secretion into bile. Cholesterol 7-hydroxylase (Cyp7a1) catalyzes the rate-limiting step in the intrahepatic conversion of cholesterol to bile acids that may have a role in HDL metabolism. We investigated the effect of Cyp7a1 deficiency on HDL metabolism in APOE*3-Leiden transgenic mice.

Methods and Results— Reduced bile acid biosynthesis in Cyp7a1–/–.APOE*3-Leiden mice versus APOE*3-Leiden mice did not affect total plasma cholesterol levels, but the distribution of cholesterol over various lipoproteins was different. Cholesterol was decreased in apoB-containing lipoproteins (ie, VLDL and IDL/LDL), whereas cholesterol was increased in HDL. The activity of PLTP and LCAT, which play a role in HDL catabolism, were not changed, and neither was HDL clearance. However, the hepatic cholesterol content was 2-fold increased, which was accompanied by a 2-fold elevated expression of hepatic ABCA1 and increased rate of cholesterol efflux from the liver to HDL.

Conclusions— Strongly reduced bile acid synthesis in Cyp7a1–/–.APOE*3-Leiden mice leads to increased plasma HDL-cholesterol levels, as related to an increased hepatic expression of ABCA1.

High levels of plasma HDL-cholesterol are correlated with a low risk of cardiovascular disease. We show that strongly reduced bile acid formation in APOE*3-Leiden transgenic mice by cholesterol 7-hydroxylase (Cyp7a1)-deficiency increases HDL-cholesterol. The clearance of HDL was not changed but hepatic ABCA1 mRNA expression was increased, suggesting an increased rate of cholesterol efflux from the liver to HDL.

Key Words: ATP binding cassette transporter A1 • bile acid synthesis • cholesterol 7-hydroxylase • high-density lipoprotein • transgenic mice