Novel Functions of Rab24 in Regulating Blood Glucose Homeostasis and Mitochondrial Activity in the Liver
Susanne Seitz1,2, Goetz Hartleben1,2, Natalie Kramer3, Sofiya Gancheva4, Anne Loft1,2, Martin Hrabe de Angelis5, Michael Roden4, Stephan Herzig1,2, Matthias Mann3, Jerome Gilleron6 and Anja Zeigerer1,2 1Institute for Diabetes and Cancer, Helmholtz Center Munich, 85764 Neuherberg, Germany; 2German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; 3Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, Martinsried, Germany; 4German Diabetes Center, 40225 Düsseldorf, Germany; 5Institute for Experimental Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany; 6INSERM U1065, Centre Méditerranéen de Médecine Moléculaire C3M, Université de Nice Sophia-Antipolis, 06108 Nice, France
The increase in the prevalence of type 2 diabetes has reached a qualified epidemic stage. The liver plays a central role in the development of type 2 diabetes due to its function in maintaining whole body glucose homeostasis. This is achieved by the interplay of multiple cellular modules: glucose metabolism, mitochondrial function and endocytosis. Endocytosis is required for the uptake and signal transduction of growth factors, signaling receptors and hormones. The storage or release of glucose through a tight control of glucose metabolism allows maintaining whole body glucose homeostasis. Mitochondrial activity ensures proper glucose turnover and energy balance. These modules need to be synchronized to collectively control glucose metabolism, where dysfunctions in this process promote the development of type 2 diabetes. Here, we report a novel trafficking player in the control of liver metabolism, Rab24, which functions at the intersection between endoplasmic reticulum, endosomes and mitochondria and is required for autophagosome maturation. We find Rab24 to be upregulated in livers of high-fat diet mice and in diabetic patients with fatty liver disease. Depletion of Rab24 increases mitochondrial mass and function in primary mouse hepatocytes in vitro and improves glucose clearance and serum cholesterol levels in vivo, suggesting a regulatory role on glucose and lipid metabolism. Altogether, our data provide novel insights into the intracellular regulation of liver metabolism and pave the way for their exploitation in the control of hepatic glucose homeostasis and thus the treatment of type 2 diabetes.
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