Document Detail

Activation of ER stress and mTORC1 suppresses hepatic sortilin-1 levels in obese mice.
MedLine Citation:
PMID:  22466652     Owner:  NLM     Status:  MEDLINE    
Recent GWAS have identified SNPs at a human chromosom1 locus associated with coronary artery disease risk and LDL cholesterol levels. The SNPs are also associated with altered expression of hepatic sortilin-1 (SORT1), which encodes a protein thought to be involved in apoB trafficking and degradation. Here, we investigated the regulation of Sort1 expression in mouse models of obesity. Sort1 expression was markedly repressed in both genetic (ob/ob) and high-fat diet models of obesity; restoration of hepatic sortilin-1 levels resulted in reduced triglyceride and apoB secretion. Mouse models of obesity also exhibit increased hepatic activity of mammalian target of rapamycin complex 1 (mTORC1) and ER stress, and we found that administration of the mTOR inhibitor rapamycin to ob/ob mice reduced ER stress and increased hepatic sortilin-1 levels. Conversely, genetically increased hepatic mTORC1 activity was associated with repressed Sort1 and increased apoB secretion. Treating WT mice with the ER stressor tunicamycin led to marked repression of hepatic sortilin-1 expression, while administration of the chemical chaperone PBA to ob/ob mice led to amelioration of ER stress, increased sortilin-1 expression, and reduced apoB and triglyceride secretion. Moreover, the ER stress target Atf3 acted at the SORT1 promoter region as a transcriptional repressor, whereas knockdown of Atf3 mRNA in ob/ob mice led to increased hepatic sortilin-1 levels and decreased apoB and triglyceride secretion. Thus, in mouse models of obesity, induction of mTORC1 and ER stress led to repression of hepatic Sort1 and increased VLDL secretion via Atf3. This pathway may contribute to dyslipidemia in metabolic disease.
Ding Ai; Juan M Baez; Hongfeng Jiang; Donna M Conlon; Antonio Hernandez-Ono; Maria Frank-Kamenetsky; Stuart Milstein; Kevin Fitzgerald; Andrew J Murphy; Connie W Woo; Alanna Strong; Henry N Ginsberg; Ira Tabas; Daniel J Rader; Alan R Tall
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-04-02
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  122     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-05-01     Completed Date:  2012-06-29     Revised Date:  2013-09-30    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1677-87     Citation Subset:  AIM; IM    
Department of Medicine, Columbia University, New York, New York 10032, USA.
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MeSH Terms
Activating Transcription Factor 3 / genetics,  metabolism,  physiology
Adaptor Proteins, Vesicular Transport / genetics,  metabolism*
Antigens, CD95 / genetics,  metabolism
Apolipoproteins B / blood,  secretion
Base Sequence
Binding Sites
Diet, High-Fat
Endoplasmic Reticulum Stress*
Gene Expression Regulation
Lipid Metabolism
Lipoproteins, VLDL / blood,  secretion
Liver / metabolism*
Mice, Inbred C57BL
Mice, Obese
Obesity / metabolism
Promoter Regions, Genetic
Proteins / antagonists & inhibitors,  genetics,  metabolism*
Sirolimus / pharmacology
Sterol Regulatory Element Binding Protein 1 / genetics,  metabolism
Transcription, Genetic
Triglycerides / blood,  secretion
Grant Support
Reg. No./Substance:
0/Activating Transcription Factor 3; 0/Adaptor Proteins, Vesicular Transport; 0/Antigens, CD95; 0/Apolipoproteins B; 0/Atf3 protein, mouse; 0/Fas protein, mouse; 0/Lipoproteins, VLDL; 0/Proteins; 0/Srebf1 protein, mouse; 0/Sterol Regulatory Element Binding Protein 1; 0/Triglycerides; 0/mechanistic target of rapamycin complex 1; 0/sortilin; 53123-88-9/Sirolimus

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