| Inhibition of acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2) prevents dietary cholesterol-associated steatosis by enhancing hepatic triglyceride mobilization. | |
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MedLine Citation:
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PMID: 20231283 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Acyl-CoA:cholesterol O-acyl transferase 2 (ACAT2) promotes cholesterol absorption by the intestine and the secretion of cholesteryl ester-enriched very low density lipoproteins by the liver. Paradoxically, mice lacking ACAT2 also exhibit mild hypertriglyceridemia. The present study addresses the unexpected role of ACAT2 in regulation of hepatic triglyceride (TG) metabolism. Mouse models of either complete genetic deficiency or pharmacological inhibition of ACAT2 were fed low fat diets containing various amounts of cholesterol to induce hepatic steatosis. Mice genetically lacking ACAT2 in both the intestine and the liver were dramatically protected against hepatic neutral lipid (TG and cholesteryl ester) accumulation, with the greatest differences occurring in situations where dietary cholesterol was elevated. Further studies demonstrated that liver-specific depletion of ACAT2 with antisense oligonucleotides prevents dietary cholesterol-associated hepatic steatosis both in an inbred mouse model of non-alcoholic fatty liver disease (SJL/J) and in a humanized hyperlipidemic mouse model (LDLr(-/-), apoB(100/100)). All mouse models of diminished ACAT2 function showed lowered hepatic triglyceride concentrations and higher plasma triglycerides secondary to increased hepatic secretion of TG into nascent very low density lipoproteins. This work demonstrates that inhibition of hepatic ACAT2 can prevent dietary cholesterol-driven hepatic steatosis in mice. These data provide the first evidence to suggest that ACAT2-specific inhibitors may hold unexpected therapeutic potential to treat both atherosclerosis and non-alcoholic fatty liver disease. |
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Authors:
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Heather M Alger; J Mark Brown; Janet K Sawyer; Kathryn L Kelley; Ramesh Shah; Martha D Wilson; Mark C Willingham; Lawrence L Rudel |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-03-15 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 285 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2010 May |
Date Detail:
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Created Date: 2010-05-03 Completed Date: 2010-06-11 Revised Date: 2011-07-28 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 14267-74 Citation Subset: IM |
Affiliation:
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Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1040, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apolipoprotein B-100 / physiology Blotting, Western Cholesterol Esters / metabolism Cholesterol, Dietary / administration & dosage Fatty Liver / metabolism, prevention & control* Female Hyperlipidemias / metabolism, prevention & control* Liver / metabolism* Male Mice Mice, Inbred C57BL Mice, Knockout Oligonucleotides, Antisense / pharmacology RNA, Messenger / genetics, metabolism Receptors, LDL / physiology Reverse Transcriptase Polymerase Chain Reaction Sterol O-Acyltransferase / antagonists & inhibitors, physiology* Triglycerides / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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1K99-HL096166/HL/NHLBI NIH HHS; HL-49373/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Apolipoprotein B-100; 0/Cholesterol Esters; 0/Cholesterol, Dietary; 0/Oligonucleotides, Antisense; 0/RNA, Messenger; 0/Receptors, LDL; 0/Triglycerides; EC 2.3.1.26/Sterol O-Acyltransferase; EC 2.3.1.26/sterol O-acyltransferase 2 |
| Comments/Corrections | |
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