Inhibition of acyl-coenzyme A:cholesterol acyltransferase stimulates cholesterol efflux from macrophages and stimulates farnesoid X receptor in hepatocytes.
10.3858/emm.2008.40.4.407
- Author:
Sojin AN
1
;
Young Soon JANG
;
Ji Seon PARK
;
Byoung Mog KWON
;
Young Ki PAIK
;
Tae Sook JEONG
Author Information
1. National Research Laboratory of Lipid Metabolism and Atherosclerosis, Yonsei University, Seoul, Korea. tsjeong@kribb.re.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
bile;
cholesterol;
cytochrome P-450 enzyme system;
farnesoid X-activated receptor;
oleoylanilide;
sterol O-acyltransferase
- MeSH:
Anilides/*pharmacology;
Bile/metabolism;
Cells, Cultured;
Cholesterol/*metabolism;
Cholesterol Esters/metabolism;
DNA-Binding Proteins/agonists/*metabolism;
Enzyme Inhibitors/pharmacology;
Gene Expression Regulation, Enzymologic/drug effects;
Hepatocytes/*drug effects/metabolism;
Humans;
Lipid Metabolism/drug effects/genetics;
Macrophages/*drug effects/metabolism;
Models, Biological;
Oleic Acids/*pharmacology;
Receptors, Cytoplasmic and Nuclear/agonists/*metabolism;
Sterol O-Acyltransferase/*antagonists & inhibitors/physiology;
Transcription Factors/agonists/*metabolism
- From:Experimental & Molecular Medicine
2008;40(4):407-417
- CountryRepublic of Korea
- Language:English
-
Abstract:
We investigated the mechanism of spontaneous cholesterol efflux induced by acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibition, and how an alteration of cholesterol metabolism in macrophages impacts on that in HepG2 cells. Oleic acid anilide (OAA), a known ACAT inhibitor reduced lipid storage substantially by promotion of cholesterol catabolism and repression of cholesteryl ester accumulation without further increase of cytotoxicity in acetylated low-density lipoprotein-loaded THP-1 macrophages. Analysis of expressed mRNA and protein revealed that cholesterol 7alpha-hydroxylase (CYP7A1), oxysterol 7alpha- hydroxylase (CYP7B1), and cholesterol 27-hydroxylase (CYP27) were highly induced by ACAT inhibition. The presence of a functional cytochrome P450 pathway was confirmed by quantification of the biliary cholesterol mass in cell monolayers and extracelluar medium. Notably, massively secreted biliary cholesterol from macrophages suppressed the expression of CYP7 proteins in a farnesoid X receptor (FXR)-dependent manner in HepG2 cells. The findings reported here provide new insight into mechanisms of spontaneous cholesterol efflux, and suggest that ACAT inhibition may stimulate cholesterol-catabolic (cytochrome P450) pathway in lesion-macrophages, in contrast, suppress it in hepatocyte via FXR induced by biliary cholesterol (BC).
