Print Email Facebook Twitter Cholesterol 7α-Hydroxylase Deficiency in Mice on an APOE*3-Leiden Background Impairs Very-Low-Density Lipoprotein Production Title Cholesterol 7α-Hydroxylase Deficiency in Mice on an APOE*3-Leiden Background Impairs Very-Low-Density Lipoprotein Production Author Post, S.M. Groenendijk, M. Solaas, K. Rensen, P.C.N. Princen, H.M.G. TNO Preventie en Gezondheid Publication year 2004 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 188.8.131.52; Cholesterol Esters; Dgat1 protein, mouse, EC 184.108.40.206; Diacylglycerol O-Acyltransferase, EC 220.127.116.11; Ketone Bodies; Lipoproteins, VLDL; RNA, Messenger; Sterols; Triglycerides; Vitamin A, 11103-57-4; Vitamin E, 1406-18-4 Subject BiologyBiomedical ResearchBile acid biosynthesisCholesterol 7α-hydroxylaseSREBP-1Bile acidCholesterolCholesterol 7alpha monooxygenaseCholesterol esterCytochrome P450 isoenzymeMessenger RNASterolSterol regulatory element binding protein 1Unclassified drugVery low density lipoproteinVitaminAcyltransferaseAlpha tocopherolApolipoprotein E3 (Leidein)Dgat1 protein, mouseDiacylglycerol acyltransferaseRetinolAnimal experimentAnimal modelAnimal tissueAntioxidant activityBile acid synthesisCatalysisCholesterol blood levelCholesterol metabolismControlled studyEnzyme deficiencyFeces levelGeneGene expressionHyperlipidemiaKnockout mouseLipid dietLipid metabolismLipogenesisLipoprotein synthesisNonhumanSrebf1 geneTriacylglycerol blood levelAtherogenic dietBiosynthesisBloodCross breedingFecesGeneticsMetabolismMouse mutantPhysiologyAcyltransferasesAnimalsApolipoprotein E3Apolipoproteins BApolipoproteins EBile Acids and SaltsCholesterol 7-alpha-HydroxylaseCholesterol EstersCrosses, GeneticDiacylglycerol O-AcyltransferaseDiet, AtherogenicFecesFemaleHyperlipoproteinemia Type IIIKetone BodiesLipid MetabolismLipolysisLipoproteins, VLDLLiverMaleMiceMice, KnockoutRNA, MessengerSterolsTriglyceridesVitamin AVitamin E To reference this document use: http://resolver.tudelft.nl/uuid:8ee08125-6e90-4b58-95dc-68aff9f596e0 DOI https://doi.org/10.1161/01.atv.0000121572.21122.59 TNO identifier 237701 ISSN 1079-5642 Source Arteriosclerosis, Thrombosis, and Vascular Biology, 24 (4), 768-774 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.