The role of keratins in the liver

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Keratins (K) constitute a large family of cytoprotective proteins and keratin mutations predispose to development of multiple human diseases. In the liver, adult hepatocytes produce K8/K18 only, while ductal cells and hepatic progenitor cells (HPCs) also express K7/K19. K7/K19 are the most established markers of ductular reaction (DR) that consists of ductal cells and HPCs and represents the basic regenerative response of the liver to injury.In the previous funding period, we analyzed the alteration of keratins during hepatic injury and studied the impact of inherited keratin variants on the development of human liver disease. We also identified K23 as a novel DR marker and demonstrated that loss of K19 attenuates DR and promotes the development of cholestatic liver injury. These findings constitute the rationale for the current renewal proposal that will systematically analyze the role of K7/K19 in the DR as well as in DR-related liver cancer. To that end, we generated K7/K19 double-knockout animals and crossbreed them with an established murine DR and liver cancer model (Mdr2-KOs). The phenotypic characterization of the animals will be complemented with analyses of bile composition and keratin architecture. Experiments with isolated primary cells together with knockdown/transfection of individual keratins will enable a detailed functional assessment of the role of K7/K19 in the DR as well as tumor formation. The proposed studies will yield novel insights into the DR as well as the importance of keratins in regeneration and tumor formation that are emerging topics.