Division - Endocytosis & Metabolism

The liver maintains glucose and lipid homeostasis by adapting its metabolic activity to the energy needs of the body. Communication between hepatocytes and the extracellular environment mediated via endocytosis is key to such homeostasis. Endocytosis is an essential mechanism for the uptake and signal transduction of growth factors and hormones but also for regulating metabolic activities, by changing the expression of hormone receptors and nutrient transporters on the cell surface of metabolically active tissue.

New evidence suggests that the endo-lysosomal system is also involved in the regulation of metabolic gene transcription. For example, the transcription factor EB (TFEB) activates genes involved in lysosomal biogenesis, autophagy and lipid metabolism. Alternatively perturbation of Rab5, the master regulator of endosomal biogenesis, in the liver phenocopied a glycogen storage disease, called von Gierke’s disease, characterized by a Glucose-6-Phosphatase (G6Pase) deficiency leading to hypoglycemia, hepatomegaly, hypercholesterolemia, hyperlipidemia and glycogen accumulation. Conversely, metabolic activities also regulate endocytosis, since knockdown of metabolic genes in a genome-wide RNAi screen had dramatic effects on endocytic cargo. Together these findings suggest that endocytosis and metabolism are functionally coupled.

The major goal of our lab is to understand how endosomal trafficking and metabolism influence and regulate each other. For this we use high-resolution immunofluorescence microscopy in primary hepatocytes and liver tissue combined with mouse molecular genetics and cutting edge in vivo silencing to study the function of the endosomal system in disease animal models for diabetes and obesity. Using these techniques we want to unravel the cellular mechanism how external cues induce changes in cellular metabolism by altering endosomal functions and to provide new cellular tools for treatment of metabolic diseases.