Inhibition of acyl-coenzyme A

Cholesterol acyltransferase stimulates cholesterol efflux from macrophages and stimulates farnesoid X receptor in hepatocytes

Sojin An, Young Soon Jang, Ji Seon Park, Byoung Mog Kwon, Young-Ki Paik, Tae Sook Jeong

Research output: Contribution to journalArticle

13 Citations (Scopus)

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).

Original languageEnglish
Pages (from-to)407-417
Number of pages11
JournalExperimental and Molecular Medicine
Volume40
Issue number4
DOIs
Publication statusPublished - 2008 Aug 31

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Sterol O-Acyltransferase
Acyl Coenzyme A
Macrophages
Hepatocytes
Cholesterol
Acyltransferases
Cholesterol 7-alpha-Hydroxylase
Hep G2 Cells
Cytochrome P-450 Enzyme System
Mixed Function Oxygenases
Enzyme inhibition
Cholesterol Esters
Cytotoxicity
Metabolism
Proteins
Monolayers
Lipids
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

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title = "Inhibition of acyl-coenzyme A: Cholesterol acyltransferase stimulates cholesterol efflux from macrophages and stimulates farnesoid X receptor in hepatocytes",
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).",
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Inhibition of acyl-coenzyme A : Cholesterol acyltransferase stimulates cholesterol efflux from macrophages and stimulates farnesoid X receptor in hepatocytes. / An, Sojin; Jang, Young Soon; Park, Ji Seon; Kwon, Byoung Mog; Paik, Young-Ki; Jeong, Tae Sook.

In: Experimental and Molecular Medicine, Vol. 40, No. 4, 31.08.2008, p. 407-417.

Research output: Contribution to journalArticle

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AU - Paik, Young-Ki

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