Document Detail

A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans.
MedLine Citation:
PMID:  22035958     Owner:  NLM     Status:  MEDLINE    
Sterol regulatory element-binding proteins (SREBPs) activate genes involved in the synthesis and trafficking of cholesterol and other lipids and are critical for maintaining lipid homeostasis. Aberrant SREBP activity, however, can contribute to obesity, fatty liver disease, and insulin resistance, hallmarks of metabolic syndrome. Our studies identify a conserved regulatory circuit in which SREBP-1 controls genes in the one-carbon cycle, which produces the methyl donor S-adenosylmethionine (SAMe). Methylation is critical for the synthesis of phosphatidylcholine (PC), a major membrane component, and we find that blocking SAMe or PC synthesis in C. elegans, mouse liver, and human cells causes elevated SREBP-1-dependent transcription and lipid droplet accumulation. Distinct from negative regulation of SREBP-2 by cholesterol, our data suggest a feedback mechanism whereby maturation of nuclear, transcriptionally active SREBP-1 is controlled by levels of PC. Thus, nutritional or genetic conditions limiting SAMe or PC production may activate SREBP-1, contributing to human metabolic disorders.
Amy K Walker; René L Jacobs; Jennifer L Watts; Veerle Rottiers; Karen Jiang; Deirdre M Finnegan; Toshi Shioda; Malene Hansen; Fajun Yang; Lorissa J Niebergall; Dennis E Vance; Monika Tzoneva; Anne C Hart; Anders M Näär
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-10-27
Journal Detail:
Title:  Cell     Volume:  147     ISSN:  1097-4172     ISO Abbreviation:  Cell     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-11-14     Completed Date:  2012-01-17     Revised Date:  2014-09-16    
Medline Journal Info:
Nlm Unique ID:  0413066     Medline TA:  Cell     Country:  United States    
Other Details:
Languages:  eng     Pagination:  840-52     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier Inc. All rights reserved.
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MeSH Terms
Caenorhabditis elegans / metabolism*
Caenorhabditis elegans Proteins / metabolism*
Cell Line, Tumor
Endoplasmic Reticulum / metabolism
Models, Animal
Phosphatidylcholines / biosynthesis
RNA Interference
S-Adenosylmethionine / biosynthesis
Sterol Regulatory Element Binding Protein 1 / metabolism*
Transcription Factors / metabolism*
Grant Support
MOP 4487//Canadian Institutes of Health Research; MOP 5182//Canadian Institutes of Health Research; R01 DK078332/DK/NIDDK NIH HHS; R01 DK078332-01/DK/NIDDK NIH HHS; R01 DK078332-02/DK/NIDDK NIH HHS; R01 DK078332-03/DK/NIDDK NIH HHS; R01 DK078332-04/DK/NIDDK NIH HHS; R01 DK084352/DK/NIDDK NIH HHS; R01 DK093623/DK/NIDDK NIH HHS; R01 GM071449/GM/NIGMS NIH HHS; R01 GM071449-01A1/GM/NIGMS NIH HHS; R01 GM071449-02/GM/NIGMS NIH HHS; R01 GM071449-03/GM/NIGMS NIH HHS; R01 GM071449-04/GM/NIGMS NIH HHS; R01 GM071449-05/GM/NIGMS NIH HHS; R01 GM071449-05S1/GM/NIGMS NIH HHS; R01DK074114/DK/NIDDK NIH HHS; R01DK078332/DK/NIDDK NIH HHS; R01DK084352/DK/NIDDK NIH HHS; R01GM071449/GM/NIGMS NIH HHS
Reg. No./Substance:
0/Caenorhabditis elegans Proteins; 0/Phosphatidylcholines; 0/SBP-1 protein, C elegans; 0/Srebf1 protein, mouse; 0/Sterol Regulatory Element Binding Protein 1; 0/Transcription Factors; 7LP2MPO46S/S-Adenosylmethionine
Comment In:
Cell. 2011 Nov 11;147(4):719-21   [PMID:  22078872 ]

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