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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:2016.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Niacin Increases HDL by Reducing Hepatic Expression and Plasma Levels of Cholesteryl Ester Transfer Protein in APOE*3Leiden.CETP Mice

José W.A. van der Hoorn; Willeke de Haan; Jimmy F.P. Berbée; Louis M. Havekes; J. Wouter Jukema; Patrick C.N. Rensen; Hans M.G. Princen

From the Netherlands Organization for Applied Scientific Research-Quality of Life (J.W.A.v.d.H., L.M.H., H.M.G.P.), Gaubius Laboratory, Leiden, The Netherlands; and the Departments of Cardiology (J.W.A.v.d.H., L.M.H., J.W.J.) and General Internal Medicine, Endocrinology, and Metabolic Diseases (W.d.H., J.F.P.B., L.M.H., P.C.N.R.), Leiden University Medical Center, The Netherlands.

Correspondence to José van der Hoorn, Netherlands Organization for Applied Scientific Research-Quality of Life, Gaubius Laboratory, P.O. Box 2215, 2301 CE Leiden, The Netherlands. E-mail jose.vanderhoorn{at}tno.nl

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— In APOE*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.

To elucidate the mechanism underlying the HDL-raising effect of niacin, APOE*3Leiden.CETP mice received increasing doses of niacin. Niacin markedly increased HDL-cholesterol by reducing the CETP-dependent transfer of cholesterol from HDL to (V)LDL, as related to a reduced hepatic CETP expression and plasma (V)LDL pool, and by decreasing the apoAI clearance.

Key Words: APOE*3Leiden.CETP transgenic mice • CETP • HDL-cholesterol • hyperlipidemia • niacin

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Of Mice and Men: Blowing Away the Cobwebs From the Mechanism of Action of Niacin on HDL Metabolism

G.F. Watts and D.C. Chan
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