PP10 investigates human and mouse cell systems and mouse models that either lack or overexpress human WT PNPLA3 or the I148M variant, ATGL, or CGI-58 in liver cells to guide future therapeutic interventions to prevent the progression of liver injury, which otherwise leads to hepatic decompensation, liver transplantation, or death of the patients. PP10 will explore whether dysregulation of lipid hydrolysis activates pro-inflammatory and pro-fibrogenic pathways leading to portal hypertension, hepatic decompensation, and acute-on-chronic liver failure. Key findings obtained in mice and cells will be validated in cells, organoids, and tissues from patients with various stages and severities of cholestatic and fatty liver disease to assess their relevance to the pathogenesis and clinical outcomes in human disease.
