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Am J Physiol Gastrointest Liver Physiol 291: G709-G716, 2006. First published June 22, 2006; doi:10.1152/ajpgi.00126.2006
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NEUROREGULATION AND MOTILITY

Proteasome inhibition attenuates hepatic injury in the bile duct-ligated mouse

Akira Anan,1 Edwina S. Baskin-Bey,1 Hajime Isomoto,1 Justin L. Mott,1 Steven F. Bronk,1 Jeffrey H. Albrecht,2 and Gregory J. Gores1

1Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester; and 2Division of Gastroenterology, Hennepin County Medical Center, Minneapolis, Minnesota

Submitted 20 March 2006 ; accepted in final form 1 June 2006

Proteasome inhibition has recently been demonstrated to inhibit hepatic fibrogenesis in the bile duct-ligated (BDL) mouse by blocking stellate cell NF-{kappa}B activation. The effect of proteasome inhibition on liver injury, however, is unclear. Our aims were to assess the effect of the proteasome inhibitor bortezomib on liver injury in the BDL mouse. Liver injury was assessed in 7-day BDL mice treated with a single dose of bortezomib on day 4 after bile duct ligation. Despite NF-{kappa}B inhibition by bortezomib, liver injury and hepatocyte apoptosis were reduced in treated BDL mice. The antiapoptotic effect of bortezomib was likely mediated by an increase in hepatic cellular FLICE inhibitory protein (c-FLIP) levels, a potent antiapoptotic protein. Unexpectedly, numerous mitotic hepatocytes were observed in the bortezomib-treated BDL mice liver specimens. Consistent with this observation, PCNA immunoreactivity and cyclin A protein expression were also increased with bortezomib treatment. Bortezomib therapy was also associated with a decrease in numbers and activation of Kupffer cells/macrophages. In conclusion, these data suggest that the proteasome inhibitor bortezomib reduces hepatocyte injury in the BDL mouse by mechanisms associated with a reduction in hepatocyte apoptosis, a decrease in Kupffer cell/macrophage number and activation, and increased hepatocyte proliferation.

bortezomib; cellular FLICE inhibitory protein; cholestasis; hepatocyte proliferation; Kupffer cells


Address for reprint requests and other correspondence: G. J. Gores, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, Minnesota 55905 (e-mail: gores.gregory{at}mayo.edu)




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