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Title 

Inhibition of acyl-coenzyme A:cholesterol acyltransferase stimulates cholesterol efflux from macrophages and stimulates farnesoid X receptor in hepatocytes

Authors 

So Jin AnYeong Sun JangJi Sun ParkByoung-Mog KwonY K PaikTae Sook Jeong

Publisher 

Korean Society of Medical Biochemistry

Issue Date 

2008

Citation 

Experimental and Molecular Medicine, vol. 40, no. 4, pp. 407-417

Keywords 

bilecholesterolcytochrome P-450 enzyme systemfarnesoid X-activated receptoroleoyl-anilidesterol O-acyltransferaseacyl coenzyme Acholesterol acyltransferasemacrophageunclassified drug

Abstract 

We investigated the mechanism of spontaneous cholesterol efflux induced by acyl-coenzyme A:cholester-ol 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 7α-hydroxylase (CYP7A1), oxysterol 7α- 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).

ISSN 

1226-3613

Link 

http://dx.doi.org/10.3858/emm.2008.40.4.407

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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