Bid antisense attenuates bile acid-induced apoptosis and cholestatic liver injury

Hajime Higuchi, Hideyuki Miyoshi, Steven F. Bronk, Hong Zhang, Nicholas Dean, Gregory James 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 (Ipr) 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 c release. 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 Biddependent despite the absence of Fas. Bid antisense therapy is a promising approach for the treatment of cholestatic liver injury.

Original languageEnglish (US)
Pages (from-to)866-873
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume299
Issue number3
StatePublished - 2001

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Bile Acids and Salts
Hepatocytes
Death Domain Receptors
Apoptosis
Liver
Wounds and Injuries
Mitochondria
BH3 Interacting Domain Death Agonist Protein
Extrahepatic Cholestasis
Cholestasis
Cytochromes c
Green Fluorescent Proteins
Bile Ducts
Oligonucleotides
Ligation
Therapeutics

ASJC Scopus subject areas

  • Pharmacology

Cite this

Bid antisense attenuates bile acid-induced apoptosis and cholestatic liver injury. / Higuchi, Hajime; Miyoshi, Hideyuki; Bronk, Steven F.; Zhang, Hong; Dean, Nicholas; Gores, Gregory James.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 299, No. 3, 2001, p. 866-873.

Research output: Contribution to journalArticle

Higuchi, Hajime ; Miyoshi, Hideyuki ; Bronk, Steven F. ; Zhang, Hong ; Dean, Nicholas ; Gores, Gregory James. / Bid antisense attenuates bile acid-induced apoptosis and cholestatic liver injury. In: Journal of Pharmacology and Experimental Therapeutics. 2001 ; Vol. 299, No. 3. pp. 866-873.
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