Submitted on October 19, 2007
Accepted on December 30, 2007
CHOP-deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury
Nobuyuki Tamaki1, Etsuro Hatano2*, Kojiro Taura3, Masaharu Tada2, Yuzo Kodama4, Takashi Nitta2, Keiko Iwaisako2, Satoru Seo2, Akio Nakajima2, Iwao Ikai2, and Shinji Uemoto2
1 Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; , Japan
2 Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
3 Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Medicine, University of California San Diego, California, United States
4 Department of Medicine, University of California San Diego, California, United States
* To whom correspondence should be addressed. E-mail: etsu{at}kuhp.kyoto-u.ac.jp.
C/EBP homologous protein (CHOP) is a key component in endoplasmic reticulum (ER) stress-mediated apoptosis. The goal of the study was to investigate the role of CHOP in cholestatic liver injury. Acute liver injury and liver fibrosis were assessed in wild type (WT) and CHOP-deficient mice following bile duct ligation (BDL). In WT livers, BDL induced overexpression of CHOP and Bax, a downstream target in the CHOP-mediated ER stress pathway. Liver fibrosis was attenuated in CHOP-knockout mice. Expression levels of 
-smooth muscle actin and transforming growth factor 
-1 were reduced and apoptotic and necrotic hepatocyte death were both attenuated in CHOP-deficient mice. Hepatocytes were isolated from WT and CHOP-deficient mice and treated with 400 µM glycochenodeoxycholic acid (GCDCA) for 8 hours to examine bile acid-induced apoptosis and necrosis. GCDCA induced overexpression of CHOP and Bax in isolated WT hepatocytes, whereas CHOP-deficient hepatocytes had reduced cleaved caspase-3 expression and a lower propidium iodide index after GCDCA treatment. In conclusion, cholestasis induces CHOP-mediated ER stress and triggers hepatocyte cell death, and CHOP-deficiency attenuates this cell death and subsequent liver fibrosis. The results demonstrate an essential role of CHOP in development of liver fibrosis due to cholestatic liver damage.
