The role of lipid hydrolysis in the pathogenesis of cholestatic and fatty liver disease and their progression to fibrosis, cirrhosis, and liver cancer are incompletely understood. Cell systems and mouse models that either lack or overexpress human wild type PNPLA3 or the I148M variant, ATGL or CGI-58 systemically or in specific liver cells should lead to therapeutic interventions to prevent the progression of liver injury, which otherwise leads to liver transplantation or death of the patients. While previous work has mainly focused on the role of these enzymes in hepatocytes, this project specifically addresses their role in cholangiocytes and macrophages. PP10 investigates whether dysregulation of lipid hydrolysis activates pro-inflammatory, pro-fibrogenic, and pro-carcinogenic pathways. Key findings from cells and mice are validated in tissues from patients suffering from different stages and severities of cholestatic and fatty liver disease, including liver and bile duct cancer, to assess their importance for the pathogenesis and clinical outcome in human disease.
