Department of Medicine, Columbia University, New York, NY 10032, USA.
Cell Metab. 2012 May 2;15(5):739-51. doi: 10.1016/j.cmet.2012.03.002. Epub 2012 Apr 12.
Hepatic glucose production (HGP) is crucial for glucose homeostasis, but the underlying mechanisms have not been fully elucidated. Here, we show that a calcium-sensing enzyme, CaMKII, is activated in a calcium- and IP3R-dependent manner by cAMP and glucagon in primary hepatocytes and by glucagon and fasting in vivo. Genetic deficiency or inhibition of CaMKII blocks nuclear translocation of FoxO1 by affecting its phosphorylation, impairs fasting- and glucagon/cAMP-induced glycogenolysis and gluconeogenesis, and lowers blood glucose levels, while constitutively active CaMKII has the opposite effects. Importantly, the suppressive effect of CaMKII deficiency on glucose metabolism is abrogated by transduction with constitutively nuclear FoxO1, indicating that the effect of CaMKII deficiency requires nuclear exclusion of FoxO1. This same pathway is also involved in excessive HGP in the setting of obesity. These results reveal a calcium-mediated signaling pathway involved in FoxO1 nuclear localization and hepatic glucose homeostasis.
肝葡萄糖生成（HGP）对葡萄糖稳态至关重要，但潜在机制尚未完全阐明。在这里，我们表明，钙敏酶 CaMKII 在原代肝细胞中被 cAMP 和胰高血糖素以钙和 IP3R 依赖性方式激活，在体内被胰高血糖素和禁食激活。CaMKII 的遗传缺陷或抑制通过影响其磷酸化来阻止 FoxO1 的核易位，损害禁食和胰高血糖素/cAMP 诱导的糖原分解和糖异生，并降低血糖水平，而组成性激活的 CaMKII 则产生相反的效果。重要的是，通过转导组成性核 FoxO1，CaMKII 缺乏对葡萄糖代谢的抑制作用被消除，表明 CaMKII 缺乏的作用需要 FoxO1 的核排斥。该途径还参与肥胖症中 HGP 的过度产生。这些结果揭示了涉及 FoxO1 核定位和肝葡萄糖稳态的钙介导信号通路。
