NAFLD-NASH-HCC progression: mechanisms of stage-transitions and identification of time windows for prevention

• Applicant: Dr. Ahmed Ghallab
• Subject Area: Gastroenterology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 457840828

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries, which may progress to non-alcoholic steatohepatitis (NASH) and eventually to cirrhosis and hepatocellular carcinoma (HCC). Currently, there are no approved drugs for treatment of NASH, mainly because of poor understanding of the driving molecular mechanisms. In his previous work, the applicant has identified six stages how NAFLD progresses to HCC: benign steatosis, macrophage crown formation, macropinocytosis of bile, ductular reaction, functional shutdown, and tumor formation. The goal of the present project is to investigate the mechanisms of stage transitions and to identify time windows when specific preventive measures are indicated. This will be achieved by addressing the following milestones: (1) Identification of blood markers that differentiate the six stages of from NAFLD to NASH; (2) Investigation if inhibition of bile macropinocytosis and (3) reducing toxicity due to bile leakage by ductular reactions block/delay NAFLD-HCC progression, respectively; (4) test the translational relevance of the mechanisms identified in mice for patients with NASH.

• DFG Programme: Research Grants