Document Detail

Hepatic regulation of fatty acid synthase by insulin and T3: evidence for T3 genomic and nongenomic actions.
MedLine Citation:
PMID:  18682535     Owner:  NLM     Status:  MEDLINE    
Fatty acid synthase (FAS) is a key enzyme of hepatic lipogenesis responsible for the synthesis of long-chain saturated fatty acids. This enzyme is mainly regulated at the transcriptional level by nutrients and hormones. In particular, glucose, insulin, and T(3) increase FAS activity, whereas glucagon and saturated and polyunsaturated fatty acids decrease it. In the present study we show that, in liver, T(3) and insulin were able to activate FAS enzymatic activity, mRNA expression, and gene transcription. We localized the T(3) response element (TRE) that mediates the T(3) genomic effect, on the FAS promoter between -741 and -696 bp that mediates the T(3) genomic effect. We show that both T(3) and insulin regulate FAS transcription via this sequence. The TRE binds a TR/RXR heterodimer even in the absence of hormone, and this binding is increased in response to T(3) and/or insulin treatment. The use of H7, a serine/threonine kinase inhibitor, reveals that a phosphorylation mechanism is implicated in the transcriptional regulation of FAS in response to both hormones. Specifically, we show that T(3) is able to modulate FAS transcription via a nongenomic action targeting the TRE through the activation of a PI 3-kinase-ERK1/2-MAPK-dependent pathway. Insulin also targets the TRE sequence, probably via the activation of two parallel pathways: Ras/ERK1/2 MAPK and PI 3-kinase/Akt. Finally, our data suggest that the nongenomic actions of T(3) and insulin are probably common to several TREs, as we observed similar effects on a classical DR4 consensus sequence.
Anne Radenne; Murielle Akpa; Caroline Martel; Sabine Sawadogo; Daniel Mauvoisin; Catherine Mounier
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-08-05
Journal Detail:
Title:  American journal of physiology. Endocrinology and metabolism     Volume:  295     ISSN:  0193-1849     ISO Abbreviation:  Am. J. Physiol. Endocrinol. Metab.     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-10-14     Completed Date:  2008-11-17     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  100901226     Medline TA:  Am J Physiol Endocrinol Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  E884-94     Citation Subset:  IM    
Département des Sciences Biologiques, Centre de recherche BioMed, Université du Québec, CP 8888, Succursale Centreville, Montreal, Canada H36 3P8.
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MeSH Terms
1-Phosphatidylinositol 3-Kinase / metabolism
Blotting, Western
Cells, Cultured
Chick Embryo
Electrophoretic Mobility Shift Assay
Extracellular Signal-Regulated MAP Kinases / physiology
Fatty Acid Synthetase Complex / genetics,  metabolism*
Insulin / pharmacology*
Liver / drug effects,  enzymology,  physiology*
Mitogen-Activated Protein Kinases / physiology
Plasmids / genetics
Promoter Regions, Genetic / genetics
Protein Biosynthesis / drug effects
RNA, Messenger / biosynthesis,  genetics
Response Elements
Signal Transduction / physiology
Triiodothyronine / genetics,  pharmacology*
Reg. No./Substance:
0/RNA, Messenger; 11061-68-0/Insulin; 6893-02-3/Triiodothyronine; EC 3-Kinase; EC Signal-Regulated MAP Kinases; EC Protein Kinases; EC 6.-/Fatty Acid Synthetase Complex

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

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