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Apolipoprotein E*3-Leiden transgenic mice as a test model for hypolipidaemic drugs.
Arzneimittelforschung. 1998 Apr; 48(4):396-402.A

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 (up 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.

Authors+Show Affiliations

TNO-PG, Gaubius Laboratory, Leiden, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9608883

Citation

van Vlijmen, B J., et al. "Apolipoprotein E*3-Leiden Transgenic Mice as a Test Model for Hypolipidaemic Drugs." Arzneimittel-Forschung, vol. 48, no. 4, 1998, pp. 396-402.
van Vlijmen BJ, Pearce NJ, Bergö M, et al. Apolipoprotein E*3-Leiden transgenic mice as a test model for hypolipidaemic drugs. Arzneimittelforschung. 1998;48(4):396-402.
van Vlijmen, B. J., 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. (1998). Apolipoprotein E*3-Leiden transgenic mice as a test model for hypolipidaemic drugs. Arzneimittel-Forschung, 48(4), 396-402.
van Vlijmen BJ, et al. Apolipoprotein E*3-Leiden Transgenic Mice as a Test Model for Hypolipidaemic Drugs. Arzneimittelforschung. 1998;48(4):396-402. PubMed PMID: 9608883.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Apolipoprotein E*3-Leiden transgenic mice as a test model for hypolipidaemic drugs. AU - van Vlijmen,B J, AU - Pearce,N J, AU - Bergö,M, AU - Staels,B, AU - Yates,J W, AU - Gribble,A D, AU - Bond,B C, AU - Hofker,M H, AU - Havekes,L M, AU - Groot,P H, PY - 1998/6/3/pubmed PY - 1998/6/3/medline PY - 1998/6/3/entrez SP - 396 EP - 402 JF - Arzneimittel-Forschung JO - Arzneimittelforschung VL - 48 IS - 4 N2 - 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 (up 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. SN - 0004-4172 UR - https://www.unboundmedicine.com/medline/citation/9608883/Apolipoprotein_E_3_Leiden_transgenic_mice_as_a_test_model_for_hypolipidaemic_drugs_ L2 - https://medlineplus.gov/cholesterolmedicines.html DB - PRIME DP - Unbound Medicine ER -