| Decreased expression of ARV1 results in cholesterol retention in the endoplasmic reticulum and abnormal bile acid metabolism. | |
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MedLine Citation:
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PMID: 20663892 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Endoplasmic reticulum (ER) membrane cholesterol is maintained at an optimal concentration of ∼5 mol % by the net impact of sterol synthesis, modification, and export. Arv1p was first identified in the yeast Saccharomyces cerevisiae as a key component of this homeostasis due to its probable role in intracellular sterol transport. Mammalian ARV1, which can fully complement the yeast lesion, encodes a ubiquitously expressed, resident ER protein. Repeated dosing of specific antisense oligonucleotides to ARV1 produced a marked reduction of ARV1 transcripts in liver, adipose, and to a lesser extent, intestine. This resulted in marked hypercholesterolemia, elevated serum bile acids, and activation of the hepatic farnesoid X receptor (FXR) regulatory pathway. Knockdown of ARV1 in murine liver and HepG2 cells was associated with accumulation of cholesterol in the ER at the expense of the plasma membrane and suppression of sterol regulatory element-binding proteins and their targets. These studies indicate a critical role of mammalian Arv1p in sterol movement from the ER and in the ensuing regulation of hepatic cholesterol and bile acid metabolism. |
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Authors:
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Fumin Tong; Jeffrey Billheimer; Caryn F Shechtman; Ying Liu; Roseann Crooke; Mark Graham; David E Cohen; Stephen L Sturley; Daniel J Rader |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-07-27 |
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 Oct |
Date Detail:
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Created Date: 2010-10-25 Completed Date: 2010-11-16 Revised Date: 2011-10-31 |
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: 33632-41 Citation Subset: IM |
Affiliation:
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Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bile Acids and Salts / metabolism* CHO Cells Carrier Proteins / metabolism* Cholesterol / metabolism* Cricetinae Cricetulus Endoplasmic Reticulum / metabolism* Humans Intestines / metabolism Male Membrane Proteins / metabolism* Mice Mice, Inbred C57BL Models, Biological Saccharomyces cerevisiae / metabolism Saccharomyces cerevisiae Proteins / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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DK48873/DK/NIDDK NIH HHS; DK54320/DK/NIDDK NIH HHS; DK56626/DK/NIDDK NIH HHS; HL59407/HL/NHLBI NIH HHS; T32DK007647/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/ARV1 protein, S cerevisiae; 0/ARV1 protein, human; 0/ARV1 protein, mouse; 0/Bile Acids and Salts; 0/Carrier Proteins; 0/Membrane Proteins; 0/Saccharomyces cerevisiae Proteins; 57-88-5/Cholesterol |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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