AP1: Lipidtropfen und assoziierte Proteine bei chronischen Lebererkrankungen und in der Hepatokarzinogenese

Hepatic steatosis accounts for the most frequent chronic liver diseases in western countries and predisposes for liver fibrosis and cirrhosis and for the development of HCC. Structural proteins of the PAT-/perilipin-family with its constituents perilipin, adipophilin, TIP47, S3-12 and MLDP (perilipin 1-5) are decisive factors in lipid droplet (LD) biogenesis, maintenance, and degradation. Absence of adipophilin and TIP47 prevents liver steatosis despite high fat diet.
In previous studies of human hepatocyte steatosis, we could demonstrate that, PAT-proteins are differentially expressed, and perilipin is de novo expressed. Whereas TIP47 and MLDP are recruited to small LDs in acute liver cell damage, adipophilin is a general LD-marker and the major determinant of hepatocyte steatosis, and perilipin characteristic of chronic hepatocyte steatosis. In diverse malignancies, LD-accumulation is a general trait of an altered tumor metabolism, and most prominent in HCC. Whereas perilipin is frequently down¬regulated during malignant progression, TIP47 and adipophilin are upregulated in HCCs and correlate positively with the proliferation rate. Targeted reduction of adipophilin or TIP47 lead to decreased amount of LDs and impaired cell viability in vitro. To analyse the impact of LDs for steatohepatitis, analyses of mice with hepatocyte-specific deletion of adipophilin under different diets are currently underway.
Aim of this project will be to clarify the role of LDs and associated proteins for the progression of chronic liver diseases and for hepatocarcinogenesis in order to establish specific modes of interference. Human liver specimens will be analysed for characteristic alterations of LDs and associated proteins leading to lipotoxicity in ballooned hepatocytes in alcoholic and non-alcoholic fatty liver disease, Wilson’s disease and hepatocytes infected with hepatitis C virus. To study the role of LDs for the long-term progression of steatosis and steatohepatitis, mice of both genders with hepatocyte-specific deletion of adipophilin and leptin deficiency will be treated with diets. To further the understanding of neoplastic steatogenesis, specific changes in lipids, PAT-proteins, their interaction partners, and regulatory pathways will be identified in human HCC-subtypes. Liver and HCC cell lines stably transfected with shRNAs against PATs will be tested functionally for lipolysis, steatogenesis, and viability. Mice with hepatocyte-specific deletion of adipophilin will be treated with the potent hepatocarcinogen diethylnitrosamin in combination with diets to evaluate whether interference with LDs may inhibit the progression of chronic liver diseases and the development of HCC.