Document Detail


Decreased expression of ARV1 results in cholesterol retention in the endoplasmic reticulum and abnormal bile acid metabolism.
MedLine Citation:
PMID:  20663892     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Fumin Tong; Jeffrey Billheimer; Caryn F Shechtman; Ying Liu; Roseann Crooke; Mark Graham; David E Cohen; Stephen L Sturley; Daniel J Rader
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-07-27
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-25     Completed Date:  2010-11-16     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  33632-41     Citation Subset:  IM    
Affiliation:
Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
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MeSH Terms
Descriptor/Qualifier:
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:
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:
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
Comments/Corrections

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