Geng Chao, Zhang Yinliang, Gao Yong, Tao Wufan, Zhang Huabing, Liu Xiaojun, Fang Fude, Chang Yongsheng
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences & School of Basic Medicine Peking Union Medical College, #5 Dongdansantiao, Beijing 100005, China.
State Key Laboratory of Genetic Engineering and Institute of Developmental Biology, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China.
Biochem Biophys Res Commun. 2016 Mar 18;471(4):444-9. doi: 10.1016/j.bbrc.2016.02.059. Epub 2016 Feb 20.
Previous study showed mammalian Ste20-like kinase (Mst1) may serve as target for the development of new therapies for diabetes. However, the function of Mst1 involved in liver lipid metabolism has remained elusive. In this study, we report that the liver of Mst1 knockout (Mst1(-/-)) mice showed more severe liver metabolic damage under fasting and high-fat diet than that of control mice. And fasting induced hepatic Mst1 expression. Mst1 overexpression inhibited Srebp-1c expression and increased the expression of antioxidant genes in primary hepatocytes. We also found that fasting-induced expression of hepatic Sirt1 was attenuated in Mst1(-/-) mice. Mst1 overexpression promoted Sirt1 expression, probably due to inhibiting Sirt1 ubiquitination. In summary, our study suggests that Mst1 regulates hepatic lipid metabolism by inhibiting Sirt1 ubiquitination in mice.
先前的研究表明，哺乳动物类Ste20激酶（Mst1）可能成为开发糖尿病新疗法的靶点。然而，Mst1在肝脏脂质代谢中的功能仍不清楚。在本研究中，我们报告称，与对照小鼠相比，Mst1基因敲除（Mst1(-/-)）小鼠的肝脏在禁食和高脂饮食条件下表现出更严重的肝脏代谢损伤。并且禁食可诱导肝脏Mst1表达。Mst1过表达抑制了原代肝细胞中Srebp-1c的表达，并增加了抗氧化基因的表达。我们还发现，禁食诱导的肝脏Sirt1表达在Mst1(-/-)小鼠中减弱。Mst1过表达促进了Sirt1表达，这可能是由于抑制了Sirt1的泛素化。总之，我们的研究表明，Mst1通过抑制小鼠肝脏中Sirt1的泛素化来调节肝脏脂质代谢。
