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Niacin increases HDL by reducing hepatic expression and plasma levels of cholesteryl ester transfer protein in APOE*3Leiden.CETP mice

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Author: Hoorn, J.W.A. van der · Haan, W. de · Berbée, J.P.P. · Havekes, L.M. · Jukema, J.W. · Rensen, P.C. · Princen, H.M.G.
Type:article
Date:2008
Institution: TNO Kwaliteit van Leven
Source:Arteriosclerosis, Thrombosis, and Vascular Biology, 11, 28, 2016-2022
Identifier: 241104
doi: doi:10.1161/ATVBAHA.108.171363
Keywords: APOE*3Leiden.CETP transgenic mice · CETP · HDL-cholesterol · Hyperlipidemia · Niacin · cholesterol · cholesterol ester transfer protein · high density lipoprotein · high density lipoprotein cholesterol · low density lipoprotein cholesterol · nicotinic acid · triacylglycerol · antilipemic agent · CETP protein, human · messenger RNA · animal experiment · animal model · animal tissue · blood level · cholesterol blood level · controlled study · dose response · drug dose comparison · drug mechanism · female · gene activity · gene expression regulation · hypercholesterolemia · hypertriglyceridemia · kidney · lipid transport · lipoprotein blood level · liver · mouse · mouse strain · nonhuman · particle size · plasma clearance · priority journal · protein blood level · protein function · protein transport · transgenic mouse · triacylglycerol blood level · atherosclerosis · bile · blood · chemistry · disease model · drug effect · fat intake · feces · genetics · metabolism · time · upregulation · Animals · Antilipemic Agents · Apolipoprotein A-I · Apolipoprotein E3 · Atherosclerosis · Bile · Cholesterol Ester Transfer Proteins · Cholesterol, HDL · Dietary Fats · Disease Models, Animal · Dose-Response Relationship, Drug · Feces · Female · Humans · Liver · Mice · Mice, Transgenic · Niacin · RNA, Messenger · Time Factors · Triglycerides · Up-Regulation

Abstract

Objective - Niacin potently decreases plasma triglycerides and LDL-cholesterol. In addition, niacin is the most potent HDL-cholesterol- increasing drug used in the clinic. In the present study, we aimed at elucidation of the mechanism underlying its HDL-raising effect. Methods and Results - InAPOE*3Leiden transgenic mice expressing the human CETP transgene, niacin dose-dependently decreased plasma triglycerides (up to -77%, P<0.001) and total cholesterol (up to -66%, P<0.001). Concomitantly, niacin dose-dependently increased HDL-cholesterol (up to +87%, P<0.001), plasma apoAI (up to +72%, P<0.001), as well as the HDL particle size. In contrast, in APOE*3Leiden mice, not expressing CETP, niacin also decreased total cholesterol and triglycerides but did not increase HDL-cholesterol. In fact, in APOE*3Leiden.CETP mice, niacin dose-dependently decreased the hepatic expression of CETP (up to -88%; P<0.01) as well as plasma CETP mass (up to -45%, P<0.001) and CETP activity (up to -52%, P<0.001). Additionally, niacin dose-dependently decreased the clearance of apoAI from plasma and reduced the uptake of apoAI by the kidneys (up to -90%, P<0.01). Conclusion - Niacin markedly increases HDL-cholesterol in APOE*3Leiden. CETP mice by reducing CETP activity, as related to lower hepatic CETP expression and a reduced plasma (V)LDL pool, and increases HDL-apoAI by decreasing the clearance of apoAI from plasma. © 2008 American Heart Association, Inc.