Subcellular reorganization in the development of hepatic steatosis

• Applicant: Dr. Natalie Krahmer
• Subject Area: Cell Biology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 419915267

With the worldwide obesity epidemic, the prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. NAFLD can potentially progress to non-alcoholic steatohepatitis (NASH), a more severe form of the disease characterized by fibrosis and inflammation and strongly increasing the risk for cirrhosis and hepatocellular carcinoma. So far, no pharmacological treatment is available and the cellular processes underlying disease development and progression are poorly understood. Using a systematic proteomic screen for the subcellular organelles in steatotic mice, we have previously identified a so far unknown dramatic reorganization on the organelle level. The lipid accumulation led to a loss of characteristic Golgi apparatus (GA) structure and a tethering of all GA proteins to newly formed lipid droplets (LDs), thereby strongly affecting the secretory function of the hepatocytes. The aim is now to understand this cellular reorganization on the mechanistic level. With this knowledge, we might be able to identify new therapeutic avenues to treat NAFLD or delay the progression of NASH. I will characterize the mechanism and structural basis of GA tethering to LDs. Combining proteomic and microscopy-based methods I will analyze the kinetics of GA relocalization and identify protein tethering factors. I will investigate whether signaling pathways regulate the organelle association and the role of the organelle lipid composition in this process. Specifically, I will test the hypothesis that increased lipid packing defects or specific lipid species on the LD surface lead to the sequestering of tethering proteins to the LD surface. In the next step, I will investigate the role of the GA phenotype for the development of hepatic steatosis. I will test how the loss of GA structure affects protein or lipid secretion and protein glycosylation. I will determine whether the LD-GA tethering enhances lipid accumulation or promotes inflammation and fibrosis and thereby drives the progression to NASH.

• DFG Programme: Independent Junior Research Groups