Exp Mol Med.  2008 Aug;40(4):407-417. 10.3858/emm.2008.40.4.407.

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

• An S
• Jang YS
• Park JS
• Kwon BM
• Paik YK
• Jeong TS

• KMID: 1094120
• DOI: http://doi.org/10.3858/emm.2008.40.4.407

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).

Keyword

bile; cholesterol; cytochrome P-450 enzyme system; farnesoid X-activated receptor; oleoylanilide; sterol O-acyltransferase

MeSH Terms

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