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Cholesterol 7α-Hydroxylase Deficiency in Mice on an APOE*3-Leiden Background Impairs Very-Low-Density Lipoprotein Production

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Author: Post, S.M. · Groenendijk, M. · Solaas, K. · Rensen, P.C.N. · Princen, H.M.G.
Type:article
Date:2004
Institution: TNO Preventie en Gezondheid
Source:Arteriosclerosis, Thrombosis, and Vascular Biology, 4, 24, 768-774
Identifier: 237701
doi: doi:10.1161/01.ATV.0000121572.21122.59
Keywords: Biology · Biomedical Research · Bile acid biosynthesis · Cholesterol 7α-hydroxylase · SREBP-1 · Bile acid · Cholesterol · Cholesterol 7alpha monooxygenase · Cholesterol ester · Cytochrome P450 isoenzyme · Messenger RNA · Sterol · Sterol regulatory element binding protein 1 · Unclassified drug · Very low density lipoprotein · Vitamin · Acyltransferase · Alpha tocopherol · Apolipoprotein E3 (Leidein) · Dgat1 protein, mouse · Diacylglycerol acyltransferase · Retinol · Animal experiment · Animal model · Animal tissue · Antioxidant activity · Bile acid synthesis · Catalysis · Cholesterol blood level · Cholesterol metabolism · Controlled study · Enzyme deficiency · Feces level · Gene · Gene expression · Hyperlipidemia · Knockout mouse · Lipid diet · Lipid metabolism · Lipogenesis · Lipoprotein synthesis · Nonhuman · Srebf1 gene · Triacylglycerol blood level · Atherogenic diet · Biosynthesis · Blood · Cross breeding · Feces · Genetics · Metabolism · Mouse mutant · Physiology · Acyltransferases · Animals · Apolipoprotein E3 · Apolipoproteins B · Apolipoproteins E · Bile Acids and Salts · Cholesterol 7-alpha-Hydroxylase · Cholesterol Esters · Crosses, Genetic · Diacylglycerol O-Acyltransferase · Diet, Atherogenic · Feces · Female · Hyperlipoproteinemia Type III · Ketone Bodies · Lipid Metabolism · Lipolysis · Lipoproteins, VLDL · Liver · Male · Mice · Mice, Knockout · RNA, Messenger · Sterols · Triglycerides · Vitamin A · Vitamin E

Abstract

Objective-Cholesterol 7α-hydroxylase (cyp7a1) catalyzes the rate-limiting step in conversion of cholesterol to bile acids. To study the relationship between bile acid biosynthesis and triglyceride metabolism, we cross-bred mice lacking cyp7a1 on a hyperlipidemic APOE*3-Leiden background. Methods and Results-Female mice received a chow or lipogenic diet. On both diets, fecal bile acid excretion was 70% decreased concomitantly with a 2-fold increased neutral sterol output. The differences in bile acid biosynthesis did not change plasma cholesterol levels. However, plasma triglyceride levels decreased by 41% and 38% in the cyp7a1-/- APOE*3-Leiden mice as compared with APOE*3-Leiden mice on chow and lipogenic diet, respectively. Mechanistic studies showed that very-low-density lipoprotein (VLDL)-apolipoprotein B and VLDL-triglyceride production rates were reduced in cyp7a1-/-.APOE*3-Leiden mice as compared with APOE*3-Leiden mice (-34% and -35%, respectively). Cyp7a1 deficiency also increased the hepatic cholesteryl ester and triglyceride content (2.8-fold and 2.5-fold, respectively). In addition, hepatic anti-oxidative vitamin content, which can influence VLDL-production, was lower. Hepatic mRNA analysis showed decreased expression of genes involved in lipogenesis including srebf1. Conclusions-Cyp7a1 deficiency in APOE*3-Leiden mice decreases the VLDL particle production rate, as a consequence of a strongly reduced bile acid biosynthesis, leading to a decrease in plasma triglycerides. These data underscore the close relationship between bile acid biosynthesis and triglyceride levels. Chemicals / CAS: cholesterol 7alpha monooxygenase, 9037-53-0; cholesterol, 57-88-5; acyltransferase, 9012-30-0, 9054-54-0; alpha tocopherol, 1406-18-4, 1406-70-8, 52225-20-4, 58-95-7, 59-02-9; diacylglycerol acyltransferase, 9029-98-5; retinol, 68-26-8, 82445-97-4; Acyltransferases, EC 2.3.-; apolipoprotein E3 (Leidein); Apolipoprotein E3; Apolipoproteins B; Apolipoproteins E; Bile Acids and Salts; Cholesterol 7-alpha-Hydroxylase, EC 1.14.13.17; Cholesterol Esters; Dgat1 protein, mouse, EC 2.3.1.20; Diacylglycerol O-Acyltransferase, EC 2.3.1.20; Ketone Bodies; Lipoproteins, VLDL; RNA, Messenger; Sterols; Triglycerides; Vitamin A, 11103-57-4; Vitamin E, 1406-18-4