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: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).
authors.affiliation: National Research Laboratory of Lipid Metabolism and Atherosclerosis, KRIBB, Daejeon, Korea.
authors.forename: Sojin
authors.initials: S
authors.lastname: An
authors.forename: Young-Soon
authors.initials: YS
authors.lastname: Jang
authors.forename: Ji-Seon
authors.initials: JS
authors.lastname: Park
authors.forename: Byoung-Mog
authors.initials: BM
authors.lastname: Kwon
authors.forename: Young-Ki
authors.initials: YK
authors.lastname: Paik
authors.forename: Tae-Sook
authors.initials: TS
authors.lastname: Jeong
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D001646:Bile / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000819:agonists / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008954:Models, Biological; D009829:Oleic Acids / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000502:physiology; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000813:Anilides; D002784:Cholesterol; D002788:Cholesterol Esters; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009829:Oleic Acids; D018160:Receptors, Cytoplasmic and Nuclear; D002785:Sterol O-Acyltransferase; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C038731:oleoylanilide
references.citation: Proc Soc Exp Biol Med. 1952 Dec;81(3):720-4
references.pmid: 13037778
references.citation: Arterioscler Thromb Vasc Biol. 2002 Jan;22(1):121-6
references.pmid: 11788471
references.citation: J Biol Chem. 2002 Nov 8;277(45):43271-80
references.pmid: 12215451
references.citation: J Biol Chem. 1990 Jul 15;265(20):12012-9
references.pmid: 1694852
references.citation: J Clin Invest. 1994 Jun;93(6):2463-72
references.pmid: 8200982
references.citation: J Med Chem. 1998 Mar 26;41(7):1007-10
references.pmid: 9544199
references.citation: J Biol Chem. 1995 Mar 17;270(11):5772-8
references.pmid: 7890706
references.citation: Can J Biochem Physiol. 1959 Aug;37(8):911-7
references.pmid: 13671378
references.citation: Expert Opin Drug Metab Toxicol. 2005 Aug;1(2):325-42
references.pmid: 16922646
references.citation: Atherosclerosis. 2005 Apr;179(2):229-36
references.pmid: 15777536
references.citation: Annu Rev Nutr. 2003;23:303-13
references.pmid: 12626688
references.citation: Biochem Biophys Res Commun. 2003 Oct 3;309(4):864-72
references.pmid: 13679053
references.citation: Exp Mol Med. 2005 Dec 31;37(6):559-66
references.pmid: 16391517
references.citation: Arch Biochem Biophys. 2000 Sep 15;381(2):273-7
references.pmid: 11032415
references.citation: Biochim Biophys Acta. 1995 Jun 6;1256(3):353-9
references.pmid: 7786899
references.citation: J Clin Invest. 2002 Apr;109(7):961-71
references.pmid: 11927623
references.citation: Endocr Rev. 2002 Oct;23(5):687-702
references.pmid: 12372848
references.citation: Arterioscler Thromb Vasc Biol. 1999 Sep;19(9):2199-206
references.pmid: 10479663
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11323-8
references.pmid: 16844773
references.citation: Atherosclerosis. 2002 Mar;161(1):45-54
references.pmid: 11882316
references.citation: Adv Lipid Res. 1968;6:1-68
references.pmid: 4179999
references.citation: Arterioscler Thromb Vasc Biol. 2001 Jan;21(1):13-27
references.pmid: 11145929
references.citation: J Biol Chem. 2000 Apr 14;275(15):10918-24
references.pmid: 10753890
references.citation: Am Heart J. 2006 Jul;152(1):67-74
references.pmid: 16824833
references.citation: J Med Chem. 1992 May 1;35(9):1609-17
references.pmid: 1578488
references.citation: J Lipid Res. 2004 Aug;45(8):1538-45
references.pmid: 15145977
references.citation: Biochim Biophys Acta. 2000 Dec 15;1529(1-3):142-54
references.pmid: 11111084
references.citation: J Clin Invest. 1987 Feb;79(2):418-26
references.pmid: 3805276
references.citation: Arterioscler Thromb Vasc Biol. 2005 Jan;25(1):122-7
references.pmid: 15499046
references.citation: J Lipid Res. 2003 Oct;44(10):1956-62
references.pmid: 12897188
references.citation: Proc Natl Acad Sci U S A. 1979 Jan;76(1):333-7
references.pmid: 218198
references.citation: Science. 2002 May 31;296(5573):1703-6
references.pmid: 11988537
references.citation: Cell. 1999 May 28;97(5):539-42
references.pmid: 10367881
references.citation: J Lipid Res. 2002 Apr;43(4):629-35
references.pmid: 11907146
references.citation: Arterioscler Thromb Vasc Biol. 2006 Oct;26(10):2316-21
references.pmid: 16825595
references.citation: Exp Mol Med. 2007 Aug 31;39(4):524-34
references.pmid: 17934341
references.citation: Hepatology. 1999 Aug;30(2):491-500
references.pmid: 10421659
references.citation: J Biol Chem. 2001 Oct 19;276(42):38378-87
references.pmid: 11504730
references.citation: FASEB J. 2003 Apr;17(6):746-8
references.pmid: 12594184
references.citation: Gene. 2001 Jan 10;262(1-2):257-65
references.pmid: 11179691
references.citation: J Lipid Res. 2002 Dec;43(12):2037-41
references.pmid: 12454263
references.citation: J Steroid Biochem. 1990 Aug 28;36(6):631-40
references.pmid: 2214780
references.citation: Proc Natl Acad Sci U S A. 1976 Sep;73(9):3178-82
references.pmid: 184464
references.citation: Mol Cell. 2000 Sep;6(3):517-26
references.pmid: 11030332
references.citation: Circulation. 2004 Nov 23;110(21):3372-7
references.pmid: 15533865
references.citation: Mol Endocrinol. 2002 Jul;16(7):1590-7
references.pmid: 12089353