Lipid droplets and associated proteins in chronic liver diseases and hepatocarcinogenesis

• Applicant: Professorin Dr. Beate Katharina Straub
• Subject Area: Pathology ; Gastroenterology
• Term: from 2010 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 177643687

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 hepatocellular carcinoma (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 (Straub et al., Hepatology, 2008). 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 (Straub et al., Histopathology, 2013), and perilipin characteristic of chronic hepatocyte steatosis (Pawella et al., J. Hepatol, 2014). In diverse malignancies, LD-accumulation is a general trait of an altered tumor metabolism, and most prominent in HCC (Straub et al., Modern Pathology, 2010). Whereas perilipin is frequently downregulated during malignant progression, TIP47 and adipophilin are upregulated in HCCs and correlate positively with the proliferation rate. Targeted reduction of adipophilin or TIP47 in vitro lead to decreased amount of LDs and impaired cell viability. 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, Wilsons 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 and progression of HCC.

• DFG Programme: Research Grants