Document Detail


A role for smooth endoplasmic reticulum membrane cholesterol ester in determining the intracellular location and regulation of sterol-regulatory-element-binding protein-2.
MedLine Citation:
PMID:  11513740     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cellular cholesterol homoeostasis is regulated through proteolysis of the membrane-bound precursor sterol-regulatory-element-binding protein (SREBP) that releases the mature transcription factor form, which regulates gene expression. Our aim was to identify the nature and intracellular site of the putative sterol-regulatory pool which regulates SREBP proteolysis in hamster liver. Cholesterol metabolism was modulated by feeding hamsters control chow, or a cholesterol-enriched diet, or by treatment with simvastatin or with the oral acyl-CoA:cholesterol acyltransferase inhibitor C1-1011 plus cholesterol. The effects of the different treatments on SREBP activation were confirmed by determination of the mRNAs for the low-density lipoprotein receptor and hydroxymethylglutaryl-CoA (HMG-CoA) reductase and by measurement of HMG-CoA reductase activity. The endoplasmic reticulum was isolated from livers and separated into subfractions by centrifugation in self-generating iodixanol gradients. Immunodetectable SREBP-2 accumulated in the smooth endoplasmic reticulum of cholesterol-fed animals. Cholesterol ester levels of the smooth endoplasmic reticulum membrane (but not the cholesterol levels) increased after cholesterol feeding and fell after treatment with simvastatin or C1-1011. The results suggest that an increased cellular cholesterol load causes accumulation of SREBP-2 in the smooth endoplasmic reticulum and, therefore, that membrane cholesterol ester may be one signal allowing exit of the SREBP-2/SREBP-cleavage-regulating protein complex to the Golgi.
Authors:
C R Iddon; J Wilkinson; A J Bennett; J Bennett; A M Salter; J A Higgins
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Biochemical journal     Volume:  358     ISSN:  0264-6021     ISO Abbreviation:  Biochem. J.     Publication Date:  2001 Sep 
Date Detail:
Created Date:  2001-08-21     Completed Date:  2001-10-04     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  England    
Other Details:
Languages:  eng     Pagination:  415-22     Citation Subset:  IM    
Affiliation:
Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2TN, UK.
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MeSH Terms
Descriptor/Qualifier:
Acetates*
Animals
Cholesterol / analysis
Cholesterol Esters / metabolism*
Cricetinae
DNA-Binding Proteins / genetics,  metabolism*
Diet, Atherogenic
Endoplasmic Reticulum, Smooth / physiology*
Enzyme Inhibitors / pharmacology
Hydroxymethylglutaryl CoA Reductases / genetics,  metabolism
Intracellular Membranes / chemistry
Liver / metabolism
Mesocricetus
RNA, Messenger / biosynthesis
Receptors, LDL / biosynthesis,  genetics
Simvastatin / pharmacology
Sterol O-Acyltransferase / antagonists & inhibitors
Sterol Regulatory Element Binding Protein 2
Sulfonic Acids / pharmacology
Transcription Factors / genetics,  metabolism*
Triglycerides / analysis
Chemical
Reg. No./Substance:
0/Acetates; 0/Cholesterol Esters; 0/DNA-Binding Proteins; 0/Enzyme Inhibitors; 0/RNA, Messenger; 0/Receptors, LDL; 0/Sterol Regulatory Element Binding Protein 2; 0/Sulfonic Acids; 0/Transcription Factors; 0/Triglycerides; 166518-60-1/avasimibe; 57-88-5/Cholesterol; 79902-63-9/Simvastatin; EC 1.1.1.-/Hydroxymethylglutaryl CoA Reductases; EC 2.3.1.26/Sterol O-Acyltransferase
Comments/Corrections

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