Abstract 8817: Niacin Promotes Macrophage Reverse Cholesterol Transport in Hypercholesterolemic Mice In a CETP-Dependent Manner

Abstract

Background- Niacin is the most effective drug currently available to increase HDL-cholesterol. The aim of the present study was to examine the effect of niacin on macrophage reverse cholesterol transport (RCT), a primary atheroprotective property of HDL, and to determine the mechanisms by which this occurs. Methods and Results- Niacin increased HDL-cholesterol in homozygous LDL receptor-deficient ( Ldlr -/- ) mice expressing human cholesterol ester transfer protein (CETP) ( Ldlr -/- . CETP ), but not in the mice without CETP. Niacin promoted macrophage RCT in the mice in a CETP-dependent manner. Treatment of Ldlr -/- . CETP mice with niacin decreased plasma CETP activity ex vivo , without the alteration of hepatic CETP expression or plasma CETP mass. Niacin also promoted macrophage RCT by reducing CETP activity even in the setting of partial lack of LDL receptor with CETP expression ( Ldlr +/- . CETP mice). Ldlr -/- . CETP mice and Ldlr +/- . CETP mice with niacin had the enhanced plasma capacity to promote macrophage cholesterol efflux. Moreover, niacin attenuated the transfer of cholesteryl esters from HDL to VLDL/LDL fractions in vivo , consistent with its inhibitory effect on CETP activity. Kinetic studies showed that niacin increased fecal excretion of HDL-derived cholesteryl esters in Ldlr -/- . CETP , but not in Ldlr -/- mice. Conclusions- Our observations demonstrate that niacin promotes macrophage RCT in vivo by decreasing plasma CETP activity in the setting of both complete and partial lack of LDL receptor. Niacin-mediated reduction in CETP activity leads to the enhanced direct pathway of RCT from HDL fractions into feces with the promotion of plasma efflux capacity from macrophages in the mice.