Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Centenary Institute, The University of Sydney, Sydney, NSW 2050, Australia.
Proc Natl Acad Sci U S A. 2020 Sep 29;117(39):24434-24442. doi: 10.1073/pnas.2007856117. Epub 2020 Sep 11.
Sphingolipid dysregulation is often associated with insulin resistance, while the enzymes controlling sphingolipid metabolism are emerging as therapeutic targets for improving insulin sensitivity. We report herein that sphingosine kinase 2 (SphK2), a key enzyme in sphingolipid catabolism, plays a critical role in the regulation of hepatic insulin signaling and glucose homeostasis both in vitro and in vivo. Hepatocyte-specific knockout mice exhibit pronounced insulin resistance and glucose intolerance. Likewise, SphK2-deficient hepatocytes are resistant to insulin-induced activation of the phosphoinositide 3-kinase (PI3K)-Akt-FoxO1 pathway and elevated hepatic glucose production. Mechanistically, SphK2 deficiency leads to the accumulation of sphingosine that, in turn, suppresses hepatic insulin signaling by inhibiting PI3K activation in hepatocytes. Either reexpressing functional SphK2 or pharmacologically inhibiting sphingosine production restores insulin sensitivity in SphK2-deficient hepatocytes. In conclusion, the current study provides both experimental findings and mechanistic data showing that SphK2 and sphingosine in the liver are critical regulators of insulin sensitivity and glucose homeostasis.
鞘脂代谢失调通常与胰岛素抵抗有关，而控制鞘脂代谢的酶正成为提高胰岛素敏感性的治疗靶点。我们在此报告，鞘氨醇激酶 2（SphK2），一种鞘脂分解代谢的关键酶，在体外和体内均对肝脏胰岛素信号和葡萄糖稳态的调节起着至关重要的作用。肝细胞特异性敲除小鼠表现出明显的胰岛素抵抗和葡萄糖不耐受。同样，SphK2 缺乏的肝细胞对胰岛素诱导的磷酸肌醇 3-激酶（PI3K）-Akt-FoxO1 途径的激活和升高的肝葡萄糖生成具有抗性。从机制上讲，SphK2 缺乏导致鞘氨醇的积累，反过来通过抑制肝细胞中 PI3K 的激活来抑制肝脏胰岛素信号。表达功能性 SphK2 或药理学抑制鞘氨醇的产生均可恢复 SphK2 缺陷肝细胞的胰岛素敏感性。总之，本研究提供了实验发现和机制数据，表明肝脏中的 SphK2 和鞘氨醇是胰岛素敏感性和葡萄糖稳态的关键调节因子。
