| Identification of ACAT1- and ACAT2-specific inhibitors using a novel, cell-based fluorescence assay: individual ACAT uniqueness. | |
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MedLine Citation:
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PMID: 14617738 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Acyl CoA:cholesterol acyltransferase 1 (ACAT1) and ACAT2 are enzymes responsible for the formation of cholesteryl esters in tissues. While both ACAT1 and ACAT2 are present in the liver and intestine, the cells containing either enzyme within these tissues are distinct, suggesting that ACAT1 and ACAT2 have separate functions. In this study, NBD-cholesterol was used to screen for specific inhibitors of ACAT1 and ACAT2. Incubation of AC29 cells, which do not contain ACAT activity, with NBD-cholesterol showed weak fluorescence when the compound was localized in the membrane. When AC29 cells stably transfected with either ACAT1 or ACAT2 were incubated with NBD-cholesterol, the fluorescent signal localized to the nonpolar core of cytoplasmic lipid droplets was strongly fluorescent and was correlated with two independent measures of ACAT activity. Several compounds were found to have greater inhibitory activity toward ACAT1 than ACAT2, and one compound was identified that specifically inhibits ACAT2. The demonstration of selective inhibition of ACAT1 and ACAT2 provides evidence for uniqueness in structure and function of these two enzymes. To the extent that ACAT2 is confined to hepatocytes and enterocytes, the only two cell types that secrete lipoproteins, selective inhibition of ACAT2 may prove to be most beneficial in the reduction of plasma lipoprotein cholesterol concentrations. |
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Authors:
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Aaron T Lada; Matthew Davis; Carol Kent; James Chapman; Hiroshi Tomoda; Satoshi Omura; Lawrence L Rudel |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. Date: 2003-11-16 |
Journal Detail:
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Title: Journal of lipid research Volume: 45 ISSN: 0022-2275 ISO Abbreviation: J. Lipid Res. Publication Date: 2004 Feb |
Date Detail:
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Created Date: 2004-02-10 Completed Date: 2004-09-27 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0376606 Medline TA: J Lipid Res Country: United States |
Other Details:
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Languages: eng Pagination: 378-86 Citation Subset: IM |
Affiliation:
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Department of Pathology, Arteriosclerosis Research Program, Wake Forest University School of Medicine, Winston-Salem, NC, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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4-Chloro-7-nitrobenzofurazan
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analogs & derivatives*,
metabolism Aniline Compounds / pharmacology Animals Cell Line, Tumor Cholesterol / analogs & derivatives*, metabolism Cricetinae Enzyme Inhibitors / pharmacology* Intestines / metabolism Isoenzymes / antagonists & inhibitors*, genetics, metabolism Liver / metabolism Pyridines / pharmacology Sesquiterpenes / pharmacology Spectrometry, Fluorescence / methods* Sterol O-Acyltransferase / antagonists & inhibitors*, genetics, metabolism Substrate Specificity / physiology Sulfides / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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HL-24736/HL/NHLBI NIH HHS; HL-49373/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/7-nitrobenz-2-oxa-1,3-diazol-4-ylcholesterol; 0/Aniline Compounds; 0/CP 113; 0/Enzyme Inhibitors; 0/Isoenzymes; 0/Pyridines; 0/Sesquiterpenes; 0/Sulfides; 10199-89-0/4-Chloro-7-nitrobenzofurazan; 147444-03-9/pyripyropene A; 57-88-5/Cholesterol; EC 2.3.1.26/Sterol O-Acyltransferase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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