Characterization of the cell type-specific role of protease-activated receptor 4 in the course of MASLD and its progression

• Applicant: Professor Dr. Johannes Georg Bode
• Subject Area: Gastroenterology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 570880952

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most common liver diseases worldwide, affecting more than 30% of the population. In approximately 3 % of cases, it progresses to steatohepatitis (MASH). Due to the high prevalence of MASLD, it can be assumed that MASH will become one of the most common causes of advanced liver disease in the coming decades. The pathogenic mechanisms underlying the transition from MASLD to MASH and its progression to liver fibrosis, cirrhosis and the development of hepatocellular carcinoma (HCC) are not fully understood. MASLD is thought to be an expression of a systemic inflammatory response associated with obesity and metabolic syndrome. The transition to MASH is the result of damage responses that create a persistent inflammatory environment and, via a vicious circle of tissue damage and impaired wound healing, maintain fibrogenic processes that lead to liver fibrosis and ultimately cirrhosis, promoting the development of HCC. Cells of both the innate and adaptive immune systems are involved in the underlying inflammatory response. A variety of findings underscore the crucial role of liver macrophages and changes in their composition, which are characterised in particular by the significantly decrease of tissue-resident macrophages and increased recruitment of monocyte-derived macrophages. In addition, components of the coagulation system and disturbances in bile salt metabolism play a role in the development and progression of MASH. Preliminary unpublished results from our group suggest that the activation of protease-activated receptor (PAR)4, a member of the PAR receptor family originally identified as a target structure for thrombin, is involved in the progression of MASLD to MASH, fibrosis and cirrhosis, depending on the stage of the disease. Gene expression analyses suggest that PAR4 influences the composition and function of liver macrophages in particular in this context. Furthermore, PAR4 appears to interfere with the enterohepatic bile acid cycle by mediating an increase in serum bile acid concentration and accelerating the development of fibrosis. The underlying mechanisms are as unclear as the function of PAR4 in the control of immune cell populations and the enterohepatic cycle. A more in-depth understanding of these mechanisms is relevant, not least because PAR4 antagonists are currently undergoing clinical approval. In this project, these questions will be investigated further using animal models with conditional deletion of PAR4 in myelomononuclear cell populations and in enterocytes.

• DFG Programme: Research Grants
• International Connection: USA
• Cooperation Partner: Professor Dr. Silvio Antoniak, Ph.D.