Caveolin-1 and TGF-beta crosstalk in hepatocytes in non-alcoholic fatty liver disease/ non alcoholic steatohepatitis (NAFLD/NASH)

• Applicant: Dr. Christoph Meyer
• Subject Area: Gastroenterology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 276773423

Non-alcoholic fatty liver disease (NAFLD) is a global health concern with increasing numbers especially in Western countries with an incidence of 20-30%. Frequently, inflammation and fibrotic remodeling develops in those patients (NASH) which may culminate in severe chronic liver injury with fatal prognosis. We could previously show that caveolin-1 is deregulated in chronic liver diseases. Caveolin-1 is a protein involved in endocytic processes and a potent regulator of diverse signaling pathways. Furthermore, our microarray analyses defined caveolin-1 as modulator of metabolic processes in hepatocytes. In context of chronic liver disease, abundance of TGF-beta fosters fibrogenesis. TGF-beta is a pleiotropic cytokine and fulfills a range of functions on diverse cell types. Towards hepatocytes, it can trigger epithelial to mesenchymal transition as well as control proliferation and induce apoptosis. We could previously show that caveolin-1 is a strong modulator of the TGF-beta signaling pathway in hepatocytes which determines cell fate. In the proposed project we intend to determine the influence of hepatocyte specific caveolin-1 on NASH development. In addition, we will assess the crosstalk of caveolin-1 and TGF-beta during liver disease development and progression. Finally, we will investigate how caveolin-1 is regulated during disease progression in vivo. To achieve our ambitious goals, we will make use of hepatocyte specific caveolin-1 knockout animals which will be fed a methionine/choline deficient diet to induce NAFLD/NASH. Furthermore, we will over-express caveolin-1 and/or TGF-beta (via lentiviral and adenoviral transduction in vivo) to study functional consequences on the cellular and organ level.This approach will enable us to determine the function of caveolin-1 on hepatocyte physiology and metabolism in healthy and diseased states as well as to describe in detail the regulation of TGF-beta signaling and cellular consequences in vivo. Hence, this attempt will give rational whether caveolin-1 in hepatocytes is a putative druggable target in metabolic liver disease.

• DFG Programme: Research Grants