Genesis and consequences of inborn and acquired alterations of hepatocellular keratin architecture

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Keratins 8 and 18 (K8/K18) are the major intermediate filament proteins of digestive epithelia. Adult hepatocytes are unique in that they express K8/K18 exclusively, whereas other cell types exhibit a more complex keratin expression pattern. Accordingly, K8/K18 alterations result in a predominant liver phenotype. For example, K8/K18 variants render mice susceptible to hepatic injury and predispose humans to liver disease development and progression. K8/K18 network reorganization into aggregates termed Mallory-Denk bodies (MDBs) is characteristic of various liver disorders including alcoholic and non-alcoholic steatohepatitis. We propose to study inborn and acquired alterations of hepatocellular K8/K18 architecture to define the molecular consequences of K8/K18 disorganization and to identify contexts that are particularly impacted by K8/K18 variants. The functional implications of altered keratin architecture will be examined at the cellular level and in transgenic mice expressing the two most common human K8/K18 variants. Analyses will be performed under basal conditions and in disease-relevant stress models. The mechanisms underlying keratin reorganization into MDBs will be evaluated in mice fed 3,5-diethoxycarbonyl-1,4-dihydrocollidine, an established MDB inducer. Human association studies and examination of human biopsy specimen will complement the rodent data. Our studies will enhance the understanding of the role of the K8/K18 cytoskeleton in liver disease and should lead to novel therapeutic approaches.