Document Detail

Obesity-related overexpression of fatty-acid synthase gene in adipose tissue involves sterol regulatory element-binding protein transcription factors.
MedLine Citation:
PMID:  9786926     Owner:  NLM     Status:  MEDLINE    
Elevated lipogenesis is a key determinant of exaggerated fat deposition in adipose tissue of obese Zucker rats. We previously delineated a region in the fatty-acid synthase promoter, which was responsible for obesity-related overexpression of the fatty-acid synthase (FAS) gene, by negatively regulating the activity of the downstream promoter in lean but not obese rat fat cells. The present study aimed to identify the transcriptional factors acting on this target region. First, functional analysis of mutated FAS promoter constructs in transiently transfected lean and obese rat adipocytes showed that the activity of the obesity-related region relied on the presence of a transcriptionally inactive sterol regulatory element at -150, which counteracted activation through the downstream E-box. Adenovirus-mediated overexpression of a dominant negative form of adipocyte determination and differentiation factor 1 (ADD1) was used to neutralize endogenous ADD1/ sterol regulatory element-binding protein (SREBP) transcriptional activity in fat cells, by producing inactive dimers unable to bind target DNA. With this system, we observed that overexpression of FAS in obese rat adipocytes was ADD1/SREBP-dependent. SREBP isoforms expression was assessed in lean and obese rat fat cells and showed no differences in the level of ADD1/SREBP1 mRNA. In addition, equivalent amounts of immunoreactive ADD1/SREBP1 were found in nuclear extracts from lean and obese rat fat cells. In contrast, immunoreactive SREBP2, which was very low in nuclear extracts from lean rats, was induced in obese rat fat cells. Finally, using in vitro binding studies, we showed that SREBP2 was able to displace ADD1/SREBP1 binding from the sterol regulatory element (SRE) site. Thus, we propose a mechanism for obesity-related overexpression of FAS gene in rat adipocyte. ADD1/SREBP1-activated transcription proceeding from the E-box motif is counterbalanced by a negative SRE site acting by limiting the availability of ADD1/SREBP1 in normal fat cells. The negative effect of this site is abolished in obese rat adipocyte nuclei where SREBP2 is induced and can substitute for ADD1/SREBP1 binding to the inactive SRE. These results provide evidence for the implication of SREBPs in the dysregulation of adipocyte metabolism characteristic of the obese state.
M Boizard; X Le Liepvre; P Lemarchand; F Foufelle; P Ferré; I Dugail
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  273     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1998 Oct 
Date Detail:
Created Date:  1998-12-01     Completed Date:  1998-12-01     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  29164-71     Citation Subset:  IM    
INSERM U465, Institut Biomédical des Cordeliers, 15 rue de l'Ecole de Médecine, 75006 Paris, France.
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MeSH Terms
Adipose Tissue / enzymology*
Binding, Competitive
CCAAT-Enhancer-Binding Proteins*
DNA-Binding Proteins / genetics,  metabolism
Fatty Acid Synthetase Complex / genetics*
Nuclear Proteins / metabolism
Obesity / enzymology,  genetics*
Protein Binding
Rats, Zucker
Sterol Regulatory Element Binding Protein 1
Sterol Regulatory Element Binding Protein 2
Transcription Factors / genetics,  metabolism
Transcription, Genetic*
Reg. No./Substance:
0/CCAAT-Enhancer-Binding Proteins; 0/DNA-Binding Proteins; 0/Nuclear Proteins; 0/Srebf1 protein, rat; 0/Sterol Regulatory Element Binding Protein 1; 0/Sterol Regulatory Element Binding Protein 2; 0/Transcription Factors; EC 6.-/Fatty Acid Synthetase Complex

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