Keratins as Targets in and Modulators of Liver Diseases

Abstract

The keratin cytoskeleton of hepatocytes is affected in a variety of chronic liver diseases, such as alcoholic and nonalcoholic steatohepatitis (ASH, NASH), copper toxicosis, cholestasis and hepatocellular carcinoma. In these diseases hepatocytes reveal a derangement or even loss of the cytoplasmic keratin intermediate filament cytoskeleton and formation of cytoplasmic inclusions (Mallory bodies) consisting of misfolded and aggregated keratin as well as a variety of stress proteins. Keratin gene knock-out mice demonstrated that keratins fulfil besides a structural role providing mechanical stability to hepatocytes a role as target and modulator of toxic stress responses in that keratins interact with a variety of stress-related signaling pathways, are preferred targets of stress-induced protein misfolding and are substrates for caspases. Furthermore, the identification of mutations in keratin genes in patients with liver cirrhosis suggests that keratins act as genetic modifiers in liver diseases.