Prostaglandin F2 Facilitates Hepatic Glucose Production Through CaMKII/p38/FOXO1 Signaling Pathway in Fasting and Obesity
Prostaglandin F2 Facilitates Hepatic Glucose Production Through CaMKII/p38/FOXO1 Signaling Pathway in Fasting and Obesity
复制标题
前列腺素 F-2 在禁食和肥胖中通过 CaMKII/p38/FOXO1 信号通路促进肝葡萄糖生成
DOI：
10.2337/db17-1521
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发表时间：
2018-09-01
期刊：
影响因子：
7.7
通讯作者：
Yu, Ying
中科院分区：
文献类型：
--
作者：
Wang, Yuanyang;Yan, Shuai;Yu, Ying
2型糖尿病患者的糖异生显著增加，这是空腹血糖浓度升高的原因。糖尿病患者循环中前列腺素(PG)F-2水平也显著升高；然而，PGF(2)是否以及如何调节肝脏葡萄糖代谢仍不清楚。在这里，我们证明了PGF(2)受体(F-前列腺素受体[FP])在禁食和糖尿病应激时在小鼠肝脏中上调。在小鼠中，肝脏FP受体的缺失抑制了禁食诱导的肝脏糖异生，而FP过表达则增强了肝脏的糖异生。FP激活可促进肝细胞糖异生酶(PEPCK和葡萄糖-6-磷酸酶)的表达，这种作用依赖于FOXO1。此外，FP与G(Q)偶联可诱导肝细胞内钙离子释放，进而激活钙/钙调素激活的蛋白激酶II(CaMKII)，增加FOXO1的磷酸化，进而加速其核转位。阻断p38可阻断CaMKII诱导的FOXO1核移位，并阻断FP介导的小鼠肝脏糖异生。此外，敲除肝脏FP受体改善了ob/ob小鼠的胰岛素敏感性和葡萄糖稳态。FP通过CaMKII/p38/FOXO1信号通路介导肝脏糖异生，提示FP受体可能是治疗2型糖尿病的一个有前途的靶点。
Gluconeogenesis is drastically increased in patients with type 2 diabetes and accounts for increased fasting plasma glucose concentrations. Circulating levels of prostaglandin (PG) F-2 are also markedly elevated in diabetes; however, whether and how PGF(2) regulates hepatic glucose metabolism remain unknown. Here, we demonstrated that PGF(2) receptor (F-prostanoid receptor [FP]) was upregulated in the livers of mice upon fasting- and diabetic stress. Hepatic deletion of the FP receptor suppressed fasting-induced hepatic gluconeogenesis, whereas FP overexpression enhanced hepatic gluconeogenesis in mice. FP activation promoted the expression of gluconeogenic enzymes (PEPCK and glucose-6-phosphatase) in hepatocytes in a FOXO1-dependent manner. Additionally, FP coupled with G(q) in hepatocytes to elicit Ca2+ release, which activated Ca2+/calmodulin-activated protein kinase II (CaMKII) to increase FOXO1 phosphorylation and subsequently accelerate its nuclear translocation. Blockage of p38 disrupted CaMKII-induced FOXO1 nuclear translocation and abrogated FP-mediated hepatic gluconeogenesis in mice. Moreover, knockdown of hepatic FP receptor improved insulin sensitivity and glucose homeostasis in ob/ob mice. FP-mediated hepatic gluconeogenesis via the CaMKII/p38/FOXO1 signaling pathway, indicating that the FP receptor might be a promising therapeutic target for type 2 diabetes.