Title
Apolipoprotein E*3-Leiden transgenic mice mode for hypolipidaemic drugs
Author
van Vlijmen, B.J.M.
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.
Gaubius Instituut TNO
Publication year
1998
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.
Subject
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
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http://resolver.tudelft.nl/uuid:7f6595e6-a5ea-494a-a50f-8d56c6ebde89
TNO identifier
234304
ISSN
0004-4172
Source
Arzneimittel-Forschung/Drug Research, 48 (4), 396-402
Document type
article