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Apolipoprotein E*3-Leiden transgenic mice mode for hypolipidaemic drugs

Author: Vlijmen, B.J.M. van · Pearce, N.J. · Bergö, M. · Staels, B. · Yates, J.W. · Gribble, A.D. · Bond, B.C. · Hofker, M.H. · Havekes, L.M. · Groot, P.H.E.
Type:article
Date:1998
Institution: Gaubius Instituut TNO
Source:Arzneimittel-Forschung/Drug Research, 4, 48, 396-402
Identifier: 234304
Keywords: Pharmacology · ±(3R*,5S*)3-Carboxy-11-(2,4-dichlorophenyl)-3,5-dihydroxyundecanoic acid, 5-ring lactone · CAS 154566-12-8 · Gemfibrozil · Hypolipidaemic drugs, testing in transgenic mice · Lovastatin · SB 204990, hypolipidaemic effect · 3 carboxy 11 (2,4 dichlorophenyl) 3,5 dihydroxyundecanoic acid · Antilipemic agent · Apolipoprotein c3 · Apolipoprotein e3 · Cholesterol · Gemfibrozil · High density lipoprotein · Lipoprotein lipase · Low density lipoprotein · Messenger rna · Mevinolin · Sb 204990 · Triacylglycerol · Unclassified drug · Very low density lipoprotein · Anticoagulant agent · Apolipoprotein E · Apolipoprotein E3 · Heparin · Lactone · Lipid · Messenger RNA · SB 204990 · Animal model · Animal tissue · Atherosclerosis · Cholesterol blood level · Controlled study · Dose response · Drug effect · Enzyme activity · Gene expression · Hyperlipidemia · Lipoprotein blood level · Male · Mouse · Nonhuman · Oral drug administration · Transgenic mouse · Animal · Biosynthesis · Blood · C57BL mouse · Drug screening · Genetics · Liver · Metabolism · hysiology · Animals · Anticoagulants · Antilipemic Agents · Apolipoprotein E3 · Apolipoproteins E · Cholesterol · Drug Evaluation, Preclinical · Gemfibrozil · Heparin · Lactones · Lipids · Lipoprotein Lipase · Liver · Lovastatin · Male · Mice · Mice, Inbred C57BL · Mice, Transgenic · RNA, Messenger · Triglycerides

Abstract

Apolipoprotein (APO) E*3-Leiden mice with impaired chylomicron and VLDL (very low density lipoprotein) remnant metabolism display hyperlipidaemia and atherosclerosis. In the present study, these mice were used for testing the hypolipidaemic effect of two marketed agents, lovastatin (CAS 75330-75-5) and gemfibrozil (CAS 25812-30-0) as well as a novel compound, SB 204990 (the 5- ring lactone of ±(3R*,5S*) 3-carboxy-11-(2,4-dichlorophenyl)-3,5- dihydroxyundecanoic acid, CAS 154566-12-8), a potent inhibitor of cholesterol and fatty acid synthesis at the level of ATP-Citrate lyase. APOE*3-Leiden mice were fed a saturated fat and cholesterol-rich diet supplemented with either 0.05 or 0.1% w/w of lovastatin, 0.1 or 0.2% w/w of gemfibrozil or 0.1 or 0.2% w/w of SB 204990. Lovastatin showed a dose-related decrease in plasma cholesterol levels (up to -20%) due to a lowering of LDL and HDL (low density resp. high density lipoprotein)-cholesterol (-20 and -18%, respectively), while plasma triglyceride levels were unaffected. Gemfibrozil had no effect on plasma total cholesterol levels but gave significant dose-dependent decreases in plasma (VLDL) triglyceride levels (tip to -53%). SB 204990 resulted in a dose-dependent reduction of plasma cholesterol (up to -29%) by lowering VLDL, LDL and HDL-cholesterol (-50, -20 and -20%, respectively). In addition, a strong dose dependent reduction of plasma (VLDL) triglycerides up to -43% was observed with this compound. Although the effects of gemfibrozil and SB 204990 were not simply explained by changes in a single determinant of VLDL metabolism - no effects of these drugs were seen on post-heparin plasma lipoprotein lipase activity, in vivo rate of VLDL synthesis or hepatic apoC- III mRNA levels - APOE*3-Leiden mice were found to give robust hypolipidaemic responses to these test compounds. The responsiveness to hypolipidaemic therapy combined with a clear relationship between aortic lesion size and plasma cholesterol exposure, as demonstrated previously, makes this mouse an attractive model for the testing of anti-atherosclerotic properties of hypolipidaemic drugs.