Rab4LiverMetabolism

Failure in glycemic control by hepatocytes is a pivotal event in the development of metabolic diseases such as type2-diabetes, NAFLD and NASH. However, although the complex network of transcription factors and enzymes allowing hepatocytes to reorganize their metabolic pathways for glucose homeostasis is relatively well established, it remains incompletely understood how hepatocytes integrate these extracellular changes and translate them into the non-genomic and the genomic programs for the glucose metabolic adaptation. Therefore, filling this gap in knowledge is an important challenge for fundamental knowledge and future clinical translation. I previously contributed to demonstrate that the endocytic system is involved in the regulation of glucose metabolism in hepatocytes, raising a novel concept of a role for regulators of endosomal trafficking in hepatocytes metabolic adaptation to nutritional cues. However, the identity of these specific endocytic regulators remains unknown and how they control the hepatocyte metabolism is far to be understood. Recently, I identified an endocytic component, the small GTPase Rab4b, which is controlled at the mRNA level by the nutritional cues, underlining its potential role in the regulation of glucose metabolism during the fasting to feeding transition. Taking advantage of a well-controlled culture system of primary hepatocytes I developed, that recapitulates fasted and fed conditions, as well as a mice model depleted for Rab4b specifically in hepatocytes, I will explore the role of this endocytic regulator on the regulation of glucose metabolism in vitro and in vivo. For this I will 1) determine whether Rab4b-dependent endocytosis is involved in the switch in hepatocyte glucose metabolism during the fasting-feeding transition, 2) investigate whether Rab4-dependent endocytosis is modulated between the fasting and feeding state, and 3) investigate the implication of liver Rab4b in the metabolic complications of obesity. Highlighting the feasibility of this proposal, I already obtained key preliminary results validating the important role of Rab4b in the response of hepatocyte to insulin and glucose, which are essential for the metabolic adaptation of hepatocytes to the fasting/feeding transition. In addition, the methodologies required for the success of this proposal are already established and work in my hands. Moreover, my expertise in both endocytosis and liver metabolism well positions my emerging team for the success of this proposal. This “young investigator” project will be a great opportunity for the emergence of my team on this new field at the interface between endocytosis and glucose metabolism.