title: CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury.
abstract: 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.
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Tamaki
authors.forename: Etsuro
authors.initials: E
authors.lastname: Hatano
authors.forename: Kojiro
authors.initials: K
authors.lastname: Taura
authors.forename: Masaharu
authors.initials: M
authors.lastname: Tada
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Kodama
authors.forename: Takashi
authors.initials: T
authors.lastname: Nitta
authors.forename: Keiko
authors.initials: K
authors.lastname: Iwaisako
authors.forename: Satoru
authors.initials: S
authors.lastname: Seo
authors.forename: Akio
authors.initials: A
authors.lastname: Nakajima
authors.forename: Iwao
authors.initials: I
authors.lastname: Ikai
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
mesh_terms: 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
chemical_list: 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