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

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

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Proteasome inhibition has recently been demonstrated to inhibit hepatic fibrogenesis in the bile duct-ligated (BDL) mouse by blocking stellate cell NF-κB 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-κB 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume291
Issue number4
DOIs
StatePublished - Oct 1 2006

Fingerprint

Proteasome Endopeptidase Complex
Bile Ducts
Liver
Wounds and Injuries
Hepatocytes
Proteasome Inhibitors
Kupffer Cells
CASP8 and FADD-Like Apoptosis Regulating Protein
Apoptosis
Cyclin A
Macrophage Activation
Bortezomib
Proliferating Cell Nuclear Antigen
Ligation
Proteins
Cell Count
Macrophages

Keywords

  • Bortezomib
  • Cellular FLICE inhibitory protein
  • Cholestasis
  • Hepatocyte proliferation
  • Kupffer cells

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Cite this

Proteasome inhibition attenuates hepatic injury in the bile duct-ligated mouse. / Anan, Akira; Baskin-Bey, Edwina S.; Isomoto, Hajime; Mott, Justin L; Bronk, Steven F.; Albrecht, Jeffrey H.; Gores, Gregory J.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 291, No. 4, 01.10.2006.

Research output: Contribution to journalArticle

Anan, Akira ; Baskin-Bey, Edwina S. ; Isomoto, Hajime ; Mott, Justin L ; Bronk, Steven F. ; Albrecht, Jeffrey H. ; Gores, Gregory J. / Proteasome inhibition attenuates hepatic injury in the bile duct-ligated mouse. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2006 ; Vol. 291, No. 4.
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