Document Detail

Ursodeoxycholic acid diminishes Fas-ligand-induced apoptosis in mouse hepatocytes.
MedLine Citation:
PMID:  12085348     Owner:  NLM     Status:  MEDLINE    
Ursodeoxycholic acid (UDCA) can protect hepatocytes from apoptosis induced by a variety of stimuli including anti-Fas antibody. However, in vivo the Fas receptor is activated by its natural ligand, Fas-L, whereas anti-Fas antibodies are not a physiologic stimulus. We therefore have assessed the anti-apoptotic effects of UDCA and other bile acids in a novel coculture model where apoptosis is induced in murine hepatocytes by membrane-bound Fas-L expressing fibroblasts. Primary hepatocytes were cultured overnight on collagen-coated coverslips with increasing concentrations of different bile acids and overlaid with either NIH 3T3 Fas-L(+) or Fas-L(-) expressing fibroblasts. After 6 hours cells were fixed and apoptosis was evaluated by TUNEL assay and DAPI staining using digital imaging. Fas-L protein expression and Fas trimerization were evaluated by Western blot analysis. FITC-UDCA and Mitotracker Red were used to evaluate UDCA localization with mitochondria. UDCA (up to 100 micromol/L, P <.0001), TUDCA (up to 400 micromol/L, P <.0001), and TCDCA (up to 200 micromol/L, P <.0001), but not TCA (up to 500 micromol/L), significantly protected hepatocytes in Fas-L(+) cocultures. UDCA had no significant effect on hepatocytes in Fas-L(-) cocultures. TUDCA, 50 micromol/L (P <.001) and TCDCA up to 200 micromol/L (P <.0001) also reduced the hepatocytes apoptotic rate in Fas-L(-) cocultures. Bile acids did not affect Fas-L expression in fibroblasts or Fas trimerization. FITC-UDCA colocalized with the mitochondrial probe. In conclusion, UDCA, TUDCA, and TCDCA but not TCA are capable of protecting hepatocytes from Fas-L-induced apoptosis. This protective effect is not associated with reductions in Fas trimerization, but may be related to a direct effect on the mitochondrial membrane.
Francesco Azzaroli; Wajahat Mehal; Carol J Soroka; Lin Wang; John Lee; Ian Nicholas Crispe; Nicholas Crispe; James L Boyer
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Hepatology (Baltimore, Md.)     Volume:  36     ISSN:  0270-9139     ISO Abbreviation:  Hepatology     Publication Date:  2002 Jul 
Date Detail:
Created Date:  2002-06-26     Completed Date:  2002-07-23     Revised Date:  2012-02-01    
Medline Journal Info:
Nlm Unique ID:  8302946     Medline TA:  Hepatology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  49-54     Citation Subset:  IM    
Liver Center, Department of Internal Medicine and Immunology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8019, USA.
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MeSH Terms
3T3 Cells
Antigens, CD95 / analysis,  chemistry,  metabolism
Apoptosis / drug effects*
Cells, Cultured
Coculture Techniques
Cross-Linking Reagents
Deoxycholic Acid / pharmacology
Fas Ligand Protein
Fibroblasts / chemistry,  metabolism
Fluorescent Dyes
Hepatocytes / cytology*
In Situ Nick-End Labeling
Membrane Glycoproteins / analysis,  pharmacology*
Taurochenodeoxycholic Acid / pharmacology
Ursodeoxycholic Acid / pharmacology*
Grant Support
Reg. No./Substance:
0/Antigens, CD95; 0/Cross-Linking Reagents; 0/Fas Ligand Protein; 0/Fasl protein, mouse; 0/Fluorescent Dyes; 0/Membrane Glycoproteins; 128-13-2/Ursodeoxycholic Acid; 14605-22-2/tauroursodeoxycholic acid; 516-35-8/Taurochenodeoxycholic Acid; 83-44-3/Deoxycholic Acid
Erratum In:
Hepatology. 2011 Sep 2;54(3):1114
Note: Crispe, Nicholas [corrected to Crispe, Ian Nicholas]

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

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