Inhibition of SphK2 Stimulated Hepatic Gluconeogenesis Associated with Dephosphorylation and Deacetylation of STAT3
Inhibition of SphK2 Stimulated Hepatic Gluconeogenesis Associated with Dephosphorylation and Deacetylation of STAT3
复制标题
抑制与 STAT3 去磷酸化和去乙酰化相关的 SphK2 刺激的肝糖异生
DOI：
10.1016/j.arcmed.2018.11.001
复制
发表时间：
2018
影响因子：
7.7
通讯作者：
Yanan Shi
中科院分区：
文献类型：
--
作者：
Jihong Yuan;Jiayun Qiao;Biao Mu;Laixiang Lin;Ling Qiao;Lihui Yan;Yanan Shi
鞘氨醇激酶（SphK）被认为是开发癌症和其他疾病（包括糖尿病）新型疗法的潜在靶点。作为肝脏中主要的 SphK 同工型，SphK2 在调节肝脏葡萄糖代谢中的作用知之甚少。本研究采用RNA干扰、实时RT-PCR、Western blot和免疫沉淀等方法研究SphK2对肝糖代谢的调控作用。结果。 siRNA和SphK2抑制剂ABC294640均刺激糖异生基因PEPCK和G6Pase的表达，但不刺激肝糖原分解、糖酵解和糖原合成酶的表达。抑制 SphK2 还可以阻止胰岛素抑制的 PEPCK 和 G6Pase 表达以及葡萄糖产生水平。此外，抑制 SphK2 通过减少 Tyr705 的磷酸化和赖氨酸残基的乙酰化来灭活 STAT3，并刺激 PEPCK 和 G6Pase 表达。 SphK2 的抑制还可以阻止 IL-6 依赖性的 STAT3 激活以及体外和体内 PEPCK 和 G6pase 表达的抑制。我们的研究表明，SphK2 参与与 STAT3 激活相关的肝脏葡萄糖代谢。
Sphingosine kinase (SphK) is considered as a potential target for developing novel therapeutics of cancer and other diseases including diabetes. As the major SphK isoform in the liver, much less is known the role of SphK2 involved in regulating hepatic glucose metabolism. In this study, RNA interference, real time RT-PCR, western blot and immunoprecipitation method was used to investigate the regulation of SphK2 in hepatic glucose metabolism. Results. Both siRNA and SphK2 inhibitor ABC294640 stimulated expression of gluconeogenetic gene PEPCK and G6Pase but not enzymes of hepatic glycogenolysis, glycolysis and glycogen synthesis. Inhibition of SphK2 also prevented insulin repressed PEPCK and G6Pase expression as well as glucose production levels. Furtherly, inhibition of SphK2 inactivated STAT3 by decreasing both phosphorylation on Tyr705 and acetylation on lysine residue, and led to stimulation of PEPCK and G6Pase expression. Inhibition of SphK2 also prevented IL-6 dependent activation of STAT3 and suppression of PEPCK and G6pase expression both in vitro and in vivo. Our study suggests that SphK2 participates in hepatic glucose metabolism related to activation of STAT3.