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Cholesterol 7α-hydroxylase deficiency in mice on an APOE*3-Leiden background increases hepatic ABCA1 mRNA expression and HDL-cholesterol

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Author: Post, S.M. · Groenendijk, M. · Hoogt, C.C. van der · Fievet, C. · Luc, G. · Hoekstra, M. · Princen, H.M.G. · Staels, B. · Rensen, P.C.N.
Institution: TNO Kwaliteit van Leven
Source:Arteriosclerosis, Thrombosis, and Vascular Biology, 12, 26, 2724-2730
Identifier: 239680
doi: doi:10.1161/01.ATV.0000247260.42560.e1
Keywords: Health · Biomedical Research · High-density lipoprotein · ABC transporter A1 · High density lipoprotein cholesterol · Intermediate density lipoprotein · Low density lipoprotein · Messenger RNA · Phosphatidylcholine sterol acyltransferase · Very low density lipoprotein · Bile acid · Phospholipid transfer protein · Phospholipid transfer protein, mouse · Animal experiment · Animal tissue · Bile acid synthesis · Biosynthesis · Catabolism · Cholesterol blood level · Cholesterol metabolism · cholesterol transport · Conhuman · Protein expression · Transgenic mouse · Genetics · Metabolism · Mouse · Mouse mutant · Physiology · Animals · Apolipoprotein E3 · ATP-Binding Cassette Transporters · Bile Acids and Salts · Cholesterol 7-alpha-Hydroxylase · Cholesterol, HDL · Female · Gene Expression Regulation · Gene Expression Regulation, Enzymologic · Humans · Liver · Mice · Mice, Knockout · Mice, Transgenic · Phosphatidylcholine-Sterol O-Acyltransferase · Phospholipid Transfer Proteins · RNA, Messenger


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 7α-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. © 2006 American Heart Association, Inc. Chemicals / CAS: cholesterol 7alpha monooxygenase, 9037-53-0; phosphatidylcholine sterol acyltransferase, 9031-14-5; Apolipoprotein E3; ATP binding cassette transporter 1; ATP-Binding Cassette Transporters; Bile Acids and Salts; Cholesterol 7-alpha-Hydroxylase, EC; Cholesterol, HDL; Phosphatidylcholine-Sterol O-Acyltransferase, EC; phospholipid transfer protein, mouse; Phospholipid Transfer Proteins; RNA, Messenger