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Vol. 299, Issue 3, 866-873, December 2001

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

Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, Rochester, Minnesota (H.H., H.M., S.F.B., G.J.G.); and Isis Pharmaceuticals, Inc., Carlsbad, California (H.Z., N.D.)

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 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 Bid-dependent despite the absence of Fas. Bid antisense therapy is a promising approach for the treatment of cholestatic liver injury.

0022-3565/01/2993-0866$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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