Document Detail


Identification and localization of a fatty acid response region in the human plasminogen activator inhibitor-1 gene.
MedLine Citation:
PMID:  11116074     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The increased expression of plasminogen activator inhibitor type-1 (PAI-1) is associated with increased concentrations of fatty acids in blood and may accelerate atherogenesis in diabetes. The present study was designed to define mechanisms by which nonesterified (free) fatty acids (FFAs) augment the expression of PAI-1. FFAs increased PAI-1 protein and mRNA expression by HepG2 cells. To identify potential regulatory elements, we constructed chimeric genes by fusing 1313, 853, 610, or 328 bp of human PAI-1 5'-flanking DNA to a luciferase reporter (PAI-LUC). A 2-fold increase in luciferase activity was seen when cells were transfected with PAI-LUC 1313, 863, or 610 and exposed to FFAs. No response to FFAs was seen with PAI-LUC 328 and after deletion of a 72-bp (-599 to -528) fragment from PAI-LUC 1313. This 72-bp fragment conferred FFA responsiveness to a different (simian virus 40) promoter. Two footprinted regions were demonstrated by DNase I analysis. Gel mobility shift assays indicated specific binding of extracted proteins to an FFA response element: 5'-TG(G/C)(1-2)CTG-3'. This sequence is repeated 4 times and is similar to an Sp1-binding site. Sp1 consensus oligonucleotides inhibited binding of extracted proteins to the regulatory elements. Accordingly, FFA-induced increased expression of PAI-1 in HepG2 cells is mediated by the binding of a transcription factor or factors to the repeated fatty acid response element, 5'-TG(G/C)(1-2)CTG-3', that is highly homologous to an Sp1-binding site.
Authors:
Y Chen; J J Billadello; D J Schneider
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Arteriosclerosis, thrombosis, and vascular biology     Volume:  20     ISSN:  1524-4636     ISO Abbreviation:  Arterioscler. Thromb. Vasc. Biol.     Publication Date:  2000 Dec 
Date Detail:
Created Date:  2000-12-20     Completed Date:  2001-03-08     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9505803     Medline TA:  Arterioscler Thromb Vasc Biol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2696-701     Citation Subset:  IM    
Affiliation:
Department of Medicine, The University of Vermont (Burlington), USA.
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MeSH Terms
Descriptor/Qualifier:
Binding Sites
Chimera
Consensus Sequence
Culture Media, Conditioned
DNA Footprinting
Fatty Acids / pharmacology*
Gene Expression Regulation / drug effects
Genes, Reporter
Humans
Luciferases / genetics
Plasminogen Activator Inhibitor 1 / biosynthesis,  genetics*
Protein Binding
Proteins / isolation & purification,  metabolism
RNA, Messenger / biosynthesis
Sp1 Transcription Factor / metabolism
Transcription, Genetic
Transfection
Tumor Cells, Cultured
Chemical
Reg. No./Substance:
0/Culture Media, Conditioned; 0/Fatty Acids; 0/Plasminogen Activator Inhibitor 1; 0/Proteins; 0/RNA, Messenger; 0/Sp1 Transcription Factor; EC 1.13.12.-/Luciferases

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


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