Document Detail


Small molecule activation of lecithin cholesterol acyltransferase modulates lipoprotein metabolism in mice and hamsters.
MedLine Citation:
PMID:  22001333     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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.
Authors:
Zhu Chen; Sheng-Ping Wang; Mihajlo L Krsmanovic; Jose Castro-Perez; Karen Gagen; Vivienne Mendoza; Ray Rosa; Vinit Shah; Timothy He; Steve J Stout; Neil S Geoghagen; Sang H Lee; David G McLaren; Liangsu Wang; Thomas P Roddy; Andrew S Plump; Brian K Hubbard; Christopher J Sinz; Douglas G Johns
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-10-14
Journal Detail:
Title:  Metabolism: clinical and experimental     Volume:  -     ISSN:  1532-8600     ISO Abbreviation:  -     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-10-17     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0375267     Medline TA:  Metabolism     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011 Elsevier Inc. All rights reserved.
Affiliation:
Cardiovascular Diseases, Merck Research Laboratories, Rahway, NJ 07065, USA.
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