The impact of endosomal protein sorting on lipid metabolism and liver development

The endo-lysosomal network is an essential system in our cells that regulates the uptake and transport of substances like proteins and lipids, and is thereby crucial in maintaining cellular homeostasis. The endo-lysosomal network has mainly been studied in cellular systems, but there is growing evidence that the endo-lysosomal network also impacts physiological and metabolic processes in our body and can contribute to diseases. In this dissertation, we use mouse models and in vitro systems to investigate the role of various endo-lysosomal proteins in physiological and metabolic processes in the liver, related to diseases such as fatty liver disease, dyslipidemia, lysosomal storage diseases, and liver cancer.
We demonstrate that the endosomal protein complex Retriever plays a specific role in regulating the uptake of triglyceride-rich particles in liver cells. Additionally, we show that another endosomal protein complex, Retromer, is crucial for the uptake and transport of cholesterol in the liver, making it indispensable for regulating cholesterol balance throughout the body. This protein complex is also necessary for maintaining the proper balance between the proliferation and differentiation of liver cells and plays an important role in postnatal liver development.
In summary, the studies presented in this dissertation provide new insights into the roles of endosomal protein complexes in lipid metabolism and liver development. These studies also highlight the importance of both cell and mouse models in understanding how these protein complexes function and contribute to biological processes and the development of diseases.