CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury
- 1 February 2008
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Gastrointestinal and Liver Physiology
- Vol. 294 (2), G498-G505
- https://doi.org/10.1152/ajpgi.00482.2007
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 α-smooth muscle actin and transforming growth factor-β1 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 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.Keywords
This publication has 36 references indexed in Scilit:
- Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9Hepatology, 2007
- Alpha-1 antitrypsin Z protein (PiZ) increases hepatic fibrosis in a murine model of cholestasisHepatology, 2007
- ER stress: Can the liver cope?Journal of Hepatology, 2006
- Macrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesionsCell Metabolism, 2006
- Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosisin vivoHepatology, 2006
- Protein accumulation and neurodegeneration in the woozy mutant mouse is caused by disruption of SIL1, a cochaperone of BiPNature Genetics, 2005
- hsp70-DnaJ chaperone pair prevents nitric oxide- and CHOP-induced apoptosis by inhibiting translocation of Bax to mitochondriaCell Death & Differentiation, 2004
- Ischemia-induced neuronal cell death is mediated by the endoplasmic reticulum stress pathway involving CHOPCell Death & Differentiation, 2004
- The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophagesNature, 2003
- A simple micromethod for collagen and total protein determination in formalin-fixed paraffin-embedded sections.Journal of Histochemistry & Cytochemistry, 1985