CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury.
CCAAT/enhancer-binding protein (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 alpha-smooth muscle actin and transforming growth factor-beta1 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 microM glycochenodeoxycholic acid (GCDCA) for 8 h 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.
Tamaki
Nobuyuki
N
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
Hatano
Etsuro
E
Taura
Kojiro
K
Tada
Masaharu
M
Kodama
Yuzo
Y
Nitta
Takashi
T
Iwaisako
Keiko
K
Seo
Satoru
S
Nakajima
Akio
A
Ikai
Iwao
I
Uemoto
Shinji
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology*; D053148:Caspase 3 / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D002756:Cholagogues and Choleretics / Q000494:pharmacology; D002779:Cholestasis / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D004721:Endoplasmic Reticulum / Q000473:pathology; D005999:Glycochenodeoxycholic Acid / Q000494:pharmacology; D022781:Hepatocytes / Q000473:pathology*; D007150:Immunohistochemistry; D008026:Ligation; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D022762:CCAAT-Enhancer-Binding Proteins; D002756:Cholagogues and Choleretics; D053773:Transforming Growth Factor beta1; D051028:bcl-2-Associated X Protein; D005999:Glycochenodeoxycholic Acid; D053148:Caspase 3