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Rosuvastatin reduces plasma lipids by inhibiting VLDL production and enhancing hepatobiliary lipid excretion in ApoE*3-Leiden mice

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Author: Delsing, D.J.M. · Post, S.M. · Groenendijk, M. · Solaas, K. · Boom, H. van der · Duyvenvoorde, W. van · Wit, E.C.M. de · Bloks, V.W. · Kuipers, F. · Havekes, L.M. · Princen, H.M.G.
Type:article
Date:2005
Institution: TNO Kwaliteit van Leven
Source:Journal of Cardiovascular Pharmacology, 1, 45, 53-60
Identifier: 238294
doi: doi:10.1097/00005344-200501000-00010
Keywords: Biomedical Research · Gene expression · Lipid metabolism · Lipoproteins · Statin · diacylglycerol acyltransferase · hydroxymethylglutaryl coenzyme A reductase inhibitor · mevinolin · phospholipid · rosuvastatin · very low density lipoprotein · animal tissue · biliary excretion · cholesterol blood level · cholesterol diet · cholesterol synthesis · controlled study · enzyme activity · gene expression · hepatobiliary system · lipid blood level · lipid composition · lipid diet · lipid liver level · lipolysis · mouse · nonhuman · priority journal · rat · statistical significance · triacylglycerol blood level · Animals · Apolipoprotein E3 · Apolipoproteins B · Apolipoproteins E · Bile · Bile Acids and Salts · Cholesterol · Cholesterol, VLDL · Chromatography, High Pressure Liquid · Feces · Female · Fluorobenzenes · Hydroxymethylglutaryl-CoA Reductase Inhibitors · Liver · Mice · Mice, Transgenic · Pyrimidines · Reverse Transcriptase Polymerase Chain Reaction · RNA, Messenger · Sterols · Sulfonamides · Triglycerides

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