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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Bid Antisense Attenuates Bile Acid-Induced Apoptosis and Cholestatic Liver Injury

Hajime Higuchi, Hideyuki Miyoshi, Steven F. Bronk, Hong Zhang, Nicholas Dean and Gregory J. Gores
Journal of Pharmacology and Experimental Therapeutics December 2001, 299 (3) 866-873;
Hajime Higuchi
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Hideyuki Miyoshi
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Steven F. Bronk
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Hong Zhang
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Nicholas Dean
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Gregory J. Gores
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Abstract

Bile acids cause liver injury during cholestasis by inducing hepatocyte apoptosis by both Fas-dependent and -independent mechanisms. However, the Fas-independent apoptosis also appears to be death receptor-mediated. Because death receptor-mediated apoptosis in hepatocytes requires proapoptotic Bcl-2 BH3 domain only protein Bid, we postulated that Fas-independent but death receptor-mediated bile acid cytotoxicity would be Bid-dependent. We used Fas-deficient lymphoproliferative (lpr) mouse hepatocytes for these studies, and inhibited Bid expression using an antisense approach. Glychochenodeoxycholate (GCDC) was used to induce apoptosis. Bid cleavage and translocation to mitochondria was observed in GCDC-treated cells as assessed by immunoblot analysis and confocal imaging of Bid-green fluorescent protein, respectively. Bid translocation to mitochondria was associated with cytochrome crelease. A Bid antisense 2′-MOE modified oligonucleotide inhibited Bid expression in hepatocytes and markedly attenuated hepatocytes apoptosis by GCDC. Treatment of lpr mice with Bid antisense also ameliorated liver injury following bile duct ligation of the mice, a model of extrahepatic cholestasis. These results suggest that bile acid cytotoxicity is Bid-dependent despite the absence of Fas. Bid antisense therapy is a promising approach for the treatment of cholestatic liver injury.

Footnotes

  • This work was supported by Grant DK41876 from the National Institutes of Health, the Mayo Foundation, and by a grant from the Kanae Foundation for Life and Socio-Medical Science.

  • Abbreviations:
    GCDC
    glychochenodeoxycholate
    TRAIL-R2
    tumor necrosis factor-related apoptosis inducing ligand receptor-2
    GFP
    green fluorescent protein
    lpr
    lymphoproliferative
    DAPI
    4′,6-diamidino-2-phenylindole dihydrochloride
    ODN
    oligodeoxynucletotides
    TMRM
    tetramethylrhodamine methylester
    ALT
    alanine aminotransferase
    AS
    antisense
    BDL
    bile duct ligation
    TUNEL
    terminal deoxynucleotidyl transferase dUTP nick-end labeling
    • Received June 27, 2001.
    • Accepted September 10, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 299 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 299, Issue 3
1 Dec 2001
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Bid Antisense Attenuates Bile Acid-Induced Apoptosis and Cholestatic Liver Injury

Hajime Higuchi, Hideyuki Miyoshi, Steven F. Bronk, Hong Zhang, Nicholas Dean and Gregory J. Gores
Journal of Pharmacology and Experimental Therapeutics December 1, 2001, 299 (3) 866-873;

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Bid Antisense Attenuates Bile Acid-Induced Apoptosis and Cholestatic Liver Injury

Hajime Higuchi, Hideyuki Miyoshi, Steven F. Bronk, Hong Zhang, Nicholas Dean and Gregory J. Gores
Journal of Pharmacology and Experimental Therapeutics December 1, 2001, 299 (3) 866-873;
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