Small molecule activation of lecithin cholesterol acyltransferase modulates lipoprotein metabolism in mice and hamsters

被引：39

作者：

Chen, Zhu ^{[1
]}

Wang, Sheng-ping ^{[1
]}

Krsmanovic, Mihajlo L. ^{[1
]}

Castro-Perez, Jose ^{[1
]}

Gagen, Karen ^{[1
]}

Mendoza, Vivienne ^{[1
]}

Rosa, Ray ^{[1
]}

Shah, Vinit ^{[1
]}

He, Timothy ^{[1
]}

Stout, Steve J. ^{[1
]}

Geoghagen, Neil S. ^{[1
]}

Lee, Sang H. ^{[1
]}

McLaren, David G. ^{[1
]}

Wang, Liangsu ^{[1
]}

Roddy, Thomas P. ^{[1
]}

Plump, Andrew S. ^{[1
]}

Hubbard, Brian K. ^{[1
]}

Sinz, Christopher J. ^{[1
]}

Johns, Douglas G. ^{[1
]}

机构：

[1] Merck Res Labs, Rahway, NJ 07065 USA

来源：

METABOLISM-CLINICAL AND EXPERIMENTAL | 2012年 / 61卷 / 04期

关键词：

HIGH-DENSITY-LIPOPROTEINS; CORONARY HEART-DISEASE; ESTER TRANSFER PROTEIN; APOLIPOPROTEIN-A-I; FAMILIAL LECITHIN; DEFICIENCY SYNDROMES; PLASMA-LIPOPROTEINS; LCAT DEFICIENCY; TRANSGENIC MICE; ATHEROSCLEROSIS;

D O I：

10.1016/j.metabol.2011.08.006

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

The objective was to assess whether pharmacological activation of lecithin cholesterol acyltransferase (LCAT) could exert beneficial effects on lipoprotein metabolism. A putative small molecule activator (compound A) was used as a tool compound in in vitro and in vivo studies. Compound A increased LCAT activity in vitro in plasma from mouse, hamster, rhesus monkey, and human. To assess the acute pharmacodynamic effects of compound A, C57Bl/6 mice and hamsters received a single dose (20 mg/kg) of compound A. Both species displayed a significant increase in high-density lipoprotein cholesterol (HDLc) and a significant decrease in non-HDLc and triglycerides acutely after dosing these changes tracked with ex vivo plasma LCAT activity. To examine compound A's chronic effect on lipoprotein metabolism, hamsters received a daily dosing of vehicle or of 20 or 60 mg/kg of compound A for 2 weeks. At study termination, compound treatment resulted in a significant increase in HDLc, HDL particle size, plasma apolipoprotein A-I level, and plasma cholesteryl ester (CE) to free cholesterol ratio, and a significant reduction in very low-density lipoprotein cholesterol. The increase in plasma CE mirrored the increase in HDL CE. Triglycerides trended toward a dose-dependent decrease in very low-density lipoprotein and HDL, with multiple triglyceride species reaching statistical significance. Gallbladder bile acids content displayed a significant and more than 2-fold increase with the 60 mg/kg treatment. We characterized pharmacological activation of LCAT by a small molecule extensively for the first time, and our findings support the potential of this approach in treating dyslipidemia and atherosclerosis; our analyses also provide mechanistic insight on LCAT's role in lipoprotein metabolism. (C) 2012 Elsevier Inc. All rights reserved.

引用

页码：470 / 481

页数：12

共 38 条

[31] MARKEDLY ACCELERATED CATABOLISM OF APOLIPOPROTEIN A-II (APOA-II) AND HIGH-DENSITY-LIPOPROTEINS CONTAINING APOA-II IN CLASSIC LECITHIN - CHOLESTEROL ACYLTRANSFERASE DEFICIENCY AND FISH-EYE DISEASE [J].