title: Small molecule activation of lecithin cholesterol acyltransferase modulates lipoprotein metabolism in mice and hamsters.
abstract: 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: Cardiovascular Diseases, Merck Research Laboratories, Rahway, NJ 07065, USA. zhu_chen@merck.com
authors: Zhu
authors: Z
authors: Chen
authors: Sheng-ping
authors: SP
authors: Wang
authors: Mihajlo L
authors: ML
authors: Krsmanovic
authors: Jose
authors: J
authors: Castro-Perez
authors: Karen
authors: K
authors: Gagen
authors: Vivienne
authors: V
authors: Mendoza
authors: Ray
authors: R
authors: Rosa
authors: Vinit
authors: V
authors: Shah
authors: Timothy
authors: T
authors: He
authors: Steve J
authors: SJ
authors: Stout
authors: Neil S
authors: NS
authors: Geoghagen
authors: Sang H
authors: SH
authors: Lee
authors: David G
authors: DG
authors: McLaren
authors: Liangsu
authors: L
authors: Wang
authors: Thomas P
authors: TP
authors: Roddy
authors: Andrew S
authors: AS
authors: Plump
authors: Brian K
authors: BK
authors: Hubbard
authors: Christopher J
authors: CJ
authors: Sinz
authors: Douglas G
authors: DG
authors: Johns
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood; D002784:Cholesterol / Q000097:blood; D002788:Cholesterol Esters / Q000097:blood; D006224:Cricetinae; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology*; D005260:Female; D008074:Lipoproteins / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000097:blood; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000378:metabolism*; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
chemical_list: D001647:Bile Acids and Salts; D002788:Cholesterol Esters; C059714:HDL cholesteryl ester; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D013830:Thiadiazoles; D014280:Triglycerides; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase