Document Detail


Activated hepatic stellate cells upregulate transcription of ecto-5'-nucleotidase/CD73 via specific SP1 and SMAD promoter elements.
MedLine Citation:
PMID:  22899823     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Adenosine is a potent modulator of liver fibrosis and inflammation. Adenosine has been shown to regulate such diverse activities as chemotaxis, contraction, and matrix production in hepatic stellate cells (HSC). Ecto-5'-nucleotidase/CD73 [EC 3.1.3.5] is the rate-limiting enzyme in adenosine production. Cd73-deficient mice are resistant to experimental liver fibrosis and have impaired adenosine generation. However, cell-specific expression and regulation of CD73 within the fibrotic liver have not been defined. In particular, prior evidence demonstrating that liver myofibroblasts, the cells believed to be responsible for matrix formation in the liver, express CD73 is lacking. Thus we tested the hypothesis that HSC and portal fibroblasts (PF), cells that undergo differentiation into liver myofibroblasts, express CD73 in a regulated fashion. We found that CD73 is weakly expressed in quiescent HSC and PF but is markedly upregulated at the transcriptional level in myofibroblastic HSC and PF. We furthermore found that CD73 protein and its functional activity are strongly increased in fibrous septa in rats subjected to experimental fibrosis. To determine the mechanism for the upregulation of Cd73 gene, we cloned the rat Cd73 promoter and then used serial truncation and site-directed mutagenesis to identify key regulatory elements. We identified two consensus SP1 motifs and one SMAD binding site, each of which was necessary for Cd73 gene upregulation. In conclusion, activated HSC upregulate Cd73 gene expression, via specific SP1 and SMAD promoter elements, after myofibroblastic differentiation. The ecto-5'-nucleotidase/CD73 enzyme is a novel cellular marker of activated liver myofibroblasts in vivo and in vitro and thus represents a promising molecular target for antifibrotic therapies in liver diseases.
Authors:
Michel Fausther; Nina Sheung; Yedidya Saiman; Meena B Bansal; Jonathan A Dranoff
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-08-16
Journal Detail:
Title:  American journal of physiology. Gastrointestinal and liver physiology     Volume:  303     ISSN:  1522-1547     ISO Abbreviation:  Am. J. Physiol. Gastrointest. Liver Physiol.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-16     Completed Date:  2013-01-11     Revised Date:  2014-04-08    
Medline Journal Info:
Nlm Unique ID:  100901227     Medline TA:  Am J Physiol Gastrointest Liver Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  G904-14     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
5'-Nucleotidase / genetics*,  metabolism
Adenosine / biosynthesis
Animals
Cell Differentiation / genetics
Cells, Cultured
Hepatic Stellate Cells / metabolism*
Immunoglobulins / genetics*,  metabolism
Liver / metabolism
Liver Cirrhosis / genetics,  metabolism
Male
Myofibroblasts / metabolism
Promoter Regions, Genetic
Rats
Rats, Sprague-Dawley
Smad Proteins / genetics*,  metabolism
Transcription, Genetic
Up-Regulation / physiology*
Grant Support
ID/Acronym/Agency:
DK071745/DK/NIDDK NIH HHS; DK6047402/DK/NIDDK NIH HHS; R01 DK070849/DK/NIDDK NIH HHS; R01 DK076735/DK/NIDDK NIH HHS; R56 DK092128/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Immunoglobulins; 0/SP1 antigen; 0/Smad Proteins; EC 3.1.3.5/5'-Nucleotidase; K72T3FS567/Adenosine
Comments/Corrections

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