1918-P: YWHAB Inhibits Hepatic Gluconeogenesis through Suppression of Glucagon Signaling Pathway

Abstract

Aims/Introduction: Hyperglycemia serves as a central factor in the development and progression of metabolic diseases. Since the glucagon receptor and its antagonism have been reported to be associated with the development and progression of hyperglycemias, the factors and proteins involved in the regulation of glucagon activity and signaling are still unclear. Materials and Methods: We examined the role of YWHAB in vivo (in hepatocyte-selective Ywhab knockout and overexpressing mice) and in vitro (in mouse primary hepatocytes and human HepG2 cells). Results: In this study, we found that YWHAB was down-regulated in ob/ob mice and db/db mice. To establish function of YWHAB in glucose metabolism in vivo, we generated hepatocyte-selective Ywhab knockout mice. The knockout mice displayed impaired blood glucose homeostasis in isolated mouse primary hepatocytes, as well as the increase in glucagon-mediated hepatocytic glucose production. Overexpressing YWHAB markedly decreases the expression of key enzymes in gluconeogenesis and inactivates the glucagon signaling. Similarly, the magnifying effect on glucagon signaling of Ywhab knockout in mouse primary hepatocytes were significantly changed by the treatment of PKA inhibitor H89. Conclusions: The regulatory role of YWHAB in hepatocytes can protect against the glucagon-induced glucose production by attenuating the activation of cAMP/PKA and the expression of key enzymes in gluconeogenesis. Thus, YWHAB is a new target site identified in the control of glucagon signaling and associated metabolic diseases. Disclosure L. Wei: None. L. Ji: None. C. Zhu: None. Funding National Natural Science Foundation of China (81870603)