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Smad3 promotes hepatocellular apoptosis and hepatic fibrogenesis following chronic cholestasis
Author(s) -
Hines Ian Neil,
Kremer Michael,
Perry Ashley Wood,
Wheeler Michael D
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a189-a
Subject(s) - cholestasis , hepatic stellate cell , apoptosis , myofibroblast , tunel assay , fibrosis , medicine , liver injury , hepatocellular carcinoma , cancer research , pathology , endocrinology , chemistry , immunohistochemistry , biochemistry
TGFβ signaling through Smad3 plays a multifunctional role within the liver, promoting myofibroblast production of collagen and inducing hepatocellular apoptosis. The purpose of the current study was to evaluate the importance of Smad3 signaling during chronic cholestasis. Wild type (wt) or Smad3 −/− mice were subjected to ligation of the common bile duct (BDL) or sham surgery and allowed to recover. Twenty one days following BDL, wt mice presented with significant increases in serum transaminases and hepatocellular apoptosis as assessed by terminal UTP nick end labeling (TUNEL) as well as significant myofibroblast activation and hepatic collagen deposition. Smad3 −/− mice subjected to the same duration of cholestasis present with significant reductions in hepatocellular injury as assessed by serum aspartate aminotransferase levels and reduced hepatocellular apoptosis, findings which correlated with reduced collagen deposition but similar stellate cell activation. Together, these data demonstrate the importance of Smad3 signaling not only in the production of collagen by intrahepatic myofibroblasts but also in the induction of hepatocellular apoptosis following chronic cholestasis. Interruption of TGFβ signaling may therefore represent an important therapeutic target for the treatment of both hepatocellular injury and tissue fibrosis. This work was supported by NIH grant AA0014243.