Cholesterol 7α-hydroxylase deficiency in mice on an APOE*3-Leiden background increases hepatic ABCA1 mRNA expression and HDL-cholesterol
article
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 1.14.13.17; Cholesterol, HDL; Phosphatidylcholine-Sterol O-Acyltransferase, EC 2.3.1.43; phospholipid transfer protein, mouse; Phospholipid Transfer Proteins; RNA, Messenger
Topics
Biomedical ResearchHigh-density lipoproteinABC transporter A1High density lipoprotein cholesterolIntermediate density lipoproteinLow density lipoproteinMessenger RNAPhosphatidylcholine sterol acyltransferaseVery low density lipoproteinBile acidPhospholipid transfer proteinPhospholipid transfer protein, mouseAnimal experimentAnimal tissueBile acid synthesisBiosynthesisCatabolismCholesterol blood levelCholesterol metabolismcholesterol transportConhumanProtein expressionTransgenic mouseGeneticsMetabolismMouseMouse mutantPhysiologyAnimalsApolipoprotein E3ATP-Binding Cassette TransportersBile Acids and SaltsCholesterol 7-alpha-HydroxylaseCholesterol, HDLFemaleGene Expression RegulationGene Expression Regulation, EnzymologicHumansLiverMiceMice, KnockoutMice, TransgenicPhosphatidylcholine-Sterol O-AcyltransferasePhospholipid Transfer ProteinsRNA, Messenger
TNO Identifier
239680
ISSN
10795642
Source
Arteriosclerosis, Thrombosis, and Vascular Biology, 26(12), pp. 2724-2730.
Pages
2724-2730
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