The importance of inherited and acquired keratin alterations in liver disease
Keratins (Ks) 8 and 18 are the intermediate filaments of digestive epithelia displaying an important cytoprotective function. Accordingly, K8/K18 variants predispose humans to acute acetaminophen toxicity and chronic liver disease development/progression. Ks are also upregulated in multiple animal stress models and dysregulated keratin production is thought to precipitate in formation of Mallory-Denk bodies (MDBs) that are K-containing aggregates characteristic of chronic liver disorders such as alcoholic and non-alcoholic fatty liver disease (ALD/NAFLD). I analysed the biological importance of K8 variants using the newly generated transgenic mice overexpressing K8 G62C or K8 R341H/C. Furthermore, I studied the expression and the regulation of Ks in context of human liver diseases and the role of K8 overproduction in high-fat (HF) diet-induced liver damage. Under basal conditions, K8 G62C/K8 R341C/H mice did show obvious liver phenotype. 18 h after i.p. administration of 600mg/kg APAP, they exhibited increased liver enzymes, JNK activation and elevated levels of APAP adducts. 21 days after bile duct ligation, a model of cholestatic liver disease, all mouse strains showed a comparable extent of liver injury and fibrosis. HF diet induced development of liver injury, further keratin accumulation as well as MDB formation in K8 overexpressing mice. Hepatic K7/K8/K18 was overexpressed in patients with ALD and chronic HCV infection but not in subjects with NAFLD/chronic HBV while K19 was significantly elevated in all analysed disorders. Ks were overexpressed in subjects with moderate versus minimal inflammation and in patients with advanced liver fibrosis. In HepG2/Hep3B cells, IL-6 treatment significantly increased K8/K18 expression. Consequently, our data suggest that Ks represent type II acute-phase responsive genes in specific human liver disorders. K8 G62C/R341C/H variants predispose to acetaminophen liver toxicity, but not to development of cholestatic liver disease.
Subject HeadingsKeratins [MeSH]
Liver diseases [MeSH]