| Ursodeoxycholic acid diminishes Fas-ligand-induced apoptosis in mouse hepatocytes. | |
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MedLine Citation:
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PMID: 12085348 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Hepatology (Baltimore, Md.) Volume: 36 ISSN: 0270-9139 ISO Abbreviation: Hepatology Publication Date: 2002 Jul |
Date Detail:
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Created Date: 2002-06-26 Completed Date: 2002-07-23 Revised Date: 2012-02-01 |
Medline Journal Info:
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Nlm Unique ID: 8302946 Medline TA: Hepatology Country: United States |
Other Details:
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Languages: eng Pagination: 49-54 Citation Subset: IM |
Affiliation:
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Liver Center, Department of Internal Medicine and Immunology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8019, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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3T3 Cells Animals 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 Kinetics Membrane Glycoproteins / analysis, pharmacology* Mice Taurochenodeoxycholic Acid / pharmacology Ursodeoxycholic Acid / pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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DK 25636/DK/NIDDK NIH HHS; DK 48823/DK/NIDDK NIH HHS; P30 DK 34989/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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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 |
| Comments/Corrections | |
Erratum In:
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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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