Document Detail


N-3 polyunsaturated fatty acids suppress insulin-induced SREBP-1c transcription via reduced trans-activating capacity of LXRalpha.
MedLine Citation:
PMID:  19716432     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Insulin coordinately up-regulates lipogenic gene transcription via induction of sterol regulatory element binding protein-1c (SREBP-1c). Conversely, polyunsaturated fatty acids (PUFA) decrease lipogenic gene transcription via suppression of SREBP-1c. We therefore examined the ability of n-3 PUFA to mitigate induction of SREBP-1c and its downstream lipogenic targets by insulin in primary rat hepatocyte cultures. Insulin induced expression of SREBP-1c mRNA 5-6 fold as well as rat SREBP-1c promoter activity. These effects were prevented by the n-3 fatty acids eicosapentaenoic acid (20:5 n-3; EPA) and docosahexaenoic acid (22:6 n-3, DHA), but not by the monounsaturated fatty acid oleic acid (18:1 n-6, OLA). N-3 fatty acids also effectively prevented insulin induction of the downstream lipogenic enzyme targets fatty acid synthase (FAS) and acetyl carboxyl coenzyme acetyltransferase-1 (ACC-1), and reduced de novo lipogenesis. The SREBP-1c promoter contains an insulin response unit consisting of tandem LXRalpha response elements (LXREs) as well as sites for NF-Y, Sp1, and SREBP-1c itself. The LXREs were identified as a primary site mediating suppression of SREBP-1c transcription by n-3 PUFA. DHA effectively prevented LXRalpha-dependent activation of both the wild type SREBP-1c promoter and the synthetic LXRE-driven promoter, and significantly blunted LXRalpha-dependent activation of a Gal4-LXRalpha chimeric protein thus demonstrating that n-3 PUFA effectively mitigate induction of SREBP-1c by insulin via reduced trans-activation of LXRalpha.
Authors:
George Howell; Xiong Deng; Chandrahassa Yellaturu; Edwards A Park; Henry G Wilcox; Rajendra Raghow; Marshall B Elam
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2009-08-27
Journal Detail:
Title:  Biochimica et biophysica acta     Volume:  1791     ISSN:  0006-3002     ISO Abbreviation:  Biochim. Biophys. Acta     Publication Date:  2009 Dec 
Date Detail:
Created Date:  2009-11-03     Completed Date:  2010-01-06     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  0217513     Medline TA:  Biochim Biophys Acta     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  1190-6     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Binding Sites
Fatty Acids, Omega-3 / pharmacology*
Insulin / pharmacology*
Lipogenesis / genetics
Luciferases / metabolism
Mutation / genetics
Orphan Nuclear Receptors / agonists,  antagonists & inhibitors,  genetics*
Rats
Response Elements / genetics
Sterol Regulatory Element Binding Protein 1 / genetics*
Transcription, Genetic / drug effects*
Transcriptional Activation / drug effects*
Grant Support
ID/Acronym/Agency:
1F32DK083210-01/DK/NIDDK NIH HHS; F32 DK083210/DK/NIDDK NIH HHS; F32 DK083210-01/DK/NIDDK NIH HHS; HL 07641-14/HL/NHLBI NIH HHS; R01 DK059368/DK/NIDDK NIH HHS; R01 DK059368-07/DK/NIDDK NIH HHS; R01 DK075504/DK/NIDDK NIH HHS; R01 DK075504-01A1/DK/NIDDK NIH HHS; R01-DK75504-01/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Fatty Acids, Omega-3; 0/Insulin; 0/Orphan Nuclear Receptors; 0/Sterol Regulatory Element Binding Protein 1; 0/liver X receptor; EC 1.13.12.-/Luciferases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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