Print Email Facebook Twitter Rosuvastatin reduces plasma lipids by inhibiting VLDL production and enhancing hepatobiliary lipid excretion in ApoE*3-Leiden mice Title Rosuvastatin reduces plasma lipids by inhibiting VLDL production and enhancing hepatobiliary lipid excretion in ApoE*3-Leiden mice Author Delsing, D.J.M. Post, S.M. Groenendijk, M. Solaas, K. van der Boom, H. van Duyvenvoorde, W. de Wit, E.C.M. Bloks, V.W. Kuipers, F. Havekes, L.M. Princen, H.M.G. TNO Kwaliteit van Leven Publication year 2005 Abstract The present study was designed to investigate the lipid-lowering properties and mechanisms of action of a new HMG-CoA reductase inhibitor, rosuvastatin, in female ApoE*3-Leiden transgenic mice. Mice received a high fat/cholesterol (HFC) diet containing either rosuvastatin (O [control], 0.00125%, 0.0025%, or 0.005% [w/w]) or 0.05% (w/w) lovastatin. The highest dose of rosuvastatin reduced plasma cholesterol and triglyceride levels by 39% and 42%, respectively, compared with the HFC control. Lovastatin had no effect on plasma cholesterol and triglyceride levels. In ApoE*3-Leiden mice on a chow diet, rosuvastatin (0.005% [w/w]) decreased plasma cholesterol levels by 35% without having an effect on triglyceride levels. On a chow diet, expression of genes involved in cholesterol biosynthesis and uptake in the liver was increased by rosuvastatin. Further mechanistic studies in HFC-fed mice showed that rosuvastatin treatment resulted in decreased hepatic VLDL-triglyceride and VLDL-apolipoprotein B production. VLDL lipid composition remained unchanged, indicating a reduction in the number of VLDL particles secreted. Lipolytic activity and expression of genes involved in cholesterol and triglyceride synthesis and β-oxidation of fatty acids in the liver were not affected by rosuvastatin treatment, and hepatic lipid content did not change. However, activity of hepatic diacylglycerol acyltransferase was significantly decreased by 25% after rosuvastatin treatment. Moreover, biliary excretion of cholesterol, phospholipids, and bile acids was increased during treatment. The results indicate that rosuvastatin treatment in ApoE*3-Leiden mice on a HFC diet leads to redistribution of cholesterol and triglycerides in the body, both by reduced hepatic VLDL production and triglyceride synthesis and by enhanced hepatobiliary removal of cholesterol, bile acids, and phospholipids, resulting in substantial reductions in plasma cholesterol and triglyceride levels. Chemicals / CAS: diacylglycerol acyltransferase, 9029-98-5; mevinolin, 75330-75-5; rosuvastatin, 147098-18-8, 147098-20-2; apolipoprotein E3 (Leidein); Apolipoprotein E3; Apolipoproteins B; Apolipoproteins E; Bile Acids and Salts; Cholesterol, 57-88-5; Cholesterol, VLDL; Fluorobenzenes; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pyrimidines; RNA, Messenger; rosuvastatin, 287714-41-4; Sterols; Sulfonamides; Triglycerides Subject Biomedical ResearchGene expressionLipid metabolismLipoproteinsStatindiacylglycerol acyltransferasehydroxymethylglutaryl coenzyme A reductase inhibitormevinolinphospholipidrosuvastatinvery low density lipoproteinanimal tissuebiliary excretioncholesterol blood levelcholesterol dietcholesterol synthesiscontrolled studyenzyme activitygene expressionhepatobiliary systemlipid blood levellipid compositionlipid dietlipid liver levellipolysismousenonhumanpriority journalratstatistical significancetriacylglycerol blood levelAnimalsApolipoprotein E3Apolipoproteins BApolipoproteins EBileBile Acids and SaltsCholesterolCholesterol, VLDLChromatography, High Pressure LiquidFecesFemaleFluorobenzenesHydroxymethylglutaryl-CoA Reductase InhibitorsLiverMiceMice, TransgenicPyrimidinesReverse Transcriptase Polymerase Chain ReactionRNA, MessengerSterolsSulfonamidesTriglycerides To reference this document use: http://resolver.tudelft.nl/uuid:aea4f407-cfac-4197-b32d-2e70bdaf328f DOI https://doi.org/10.1097/00005344-200501000-00010 TNO identifier 238294 ISSN 0160-2446 Source Journal of Cardiovascular Pharmacology, 45 (1), 53-60 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.