P38 Αlpha MAPK Regulates Foxo1 and Hepatic Glucose Production in Health and Disease
Abstract
Glucagon governs hepatic glucose production (HGP) by triggering glycogenolysis and gluconeogenesis. The p38α MAPK (p38α) is activated by glucagon to promote hepatic glucose production (HGP), but underlying mechanisms have not been well elucidated. In this study, we showed that p38α is activated by glucagon through the cAMP–EPAC pathway in primary hepatocytes in control of Foxo1-S273 phosphorylation. In both hepatocytes and mice, inhibition of p38α blocked Foxo1-S273 phosphorylation, decreased Foxo1 protein level, and impaired glucagon- and fasting-induced HGP. However, the effect of p38α inhibition was abolished by Foxo1-deficiency or Foxo1-S273A or D mutation. Moreover, the p38α-regulated Foxo1 pathway plays an indispensable role in stimulating HGP in inflammatory hepatocytes and insulin resistant mice. This study reveals a novel mechanism of p38α by which it regulates Foxo1-S273 phosphorylation to mediate the action of glucagon on glucose homeostasis.
Citation
Yang, Wanbao (2020). P38 Αlpha MAPK Regulates Foxo1 and Hepatic Glucose Production in Health and Disease. Doctoral dissertation, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /192775.