Suppressor of cytokine signalling-2 controls hepatic gluconeogenesis and hyperglycemia by modulating JAK2/STAT5 signalling pathway
Suppressor of cytokine signalling-2 controls hepatic gluconeogenesis and hyperglycemia by modulating JAK2/STAT5 signalling pathway
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细胞因子信号传导抑制剂 2 通过调节 JAK2/STAT5 信号通路控制肝糖异生和高血糖
DOI：
10.1016/j.metabol.2021.154823
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发表时间：
2021
影响因子：
9.8
通讯作者：
John Zhong Li
中科院分区：
文献类型：
--
作者：
Xu Zhang;Yuan Zhuang;Tian Qin;Meijia Chang;Xuetao Ji;Ning Wang;Zhilei Zhang;Hongwen Zhou;Qian Wang;John Zhong Li
肝脏的新生在维持哺乳动物的血糖平衡中起着至关重要的作用。地球仪敲除细胞因子信号传导抑制因子-2（SOCS 2），一种细胞因子信号传导的反馈抑制剂，已被证明对高脂饮食（HFD）诱导的伴有糖耐量受损的小鼠肝脂肪变性具有抗性。然而，SOCS 2调节肝脏葡萄糖稳态的潜在机制仍不清楚。在本研究中，我们证明了禁食的C57 BL/6 J小鼠或db/db小鼠的肝脏SOCS 2表达显著降低。此外，二甲双胍处理诱导肝脏SOCS 2表达水平。SOCS 2的消融减弱了二甲双胍对肝细胞中新生血管形成的抑制作用。功能获得和功能丧失研究表明，SOCS 2通过介导JAK 2/STAT 5信号通路调节db/db小鼠肝脏致炎基因表达和葡萄糖输出。从机制上讲，我们观察到SOCS 2通过减弱JAK 2和STAT 5之间的相互作用使STAT 5失活，这反过来又减少了肝细胞再生。目前的研究揭示了SOCS 2在调节肝硬化发生中的关键作用。二甲双胍对肝硬化发生的抑制作用至少部分是通过上调SOCS 2从而降低肝硬化发生基因表达介导的。SOCS 2可能成为糖尿病治疗的新靶点。
Hepatic gluconeogenesis plays a crucial role in maintaining blood glucose homeostasis in mammals. Globe knockout of suppressor of cytokine signalling-2 (SOCS2), a feedback inhibitor of cytokine signalling, has been shown resistant to high-fat-diet (HFD)-induced hepatic steatosis with impaired glucose tolerance in mice. However, the underlying mechanism of SOCS2 regulates hepatic glucose homeostasis still undefined. In the present study, we demonstrated that the hepatic SOCS2 expression is markedly reduced in fastedC57BL/6Jmice ordb/dbmice. Moreover, hepatic SOCS2 expression levels are induced by metformin treatment. Ablation of SOCS2 attenuates suppressing effects of metformin on gluconeogenesis in hepatocytes. Gain- and loss-of-function studies indicated that SOCS2 regulates hepatic gluconeogenic genes expression and glucose output by mediating JAK2/STAT5 signalling pathway indb/dbmice. Mechanistically, we observed that SOCS2 inactivates STAT5 by attenuating the interaction between JAK2 and STAT5, which in turn reduces hepatic gluconeogenesis. The present study reveals a critical role of SOCS2 in regulating hepatic gluconeogenesis. The inhibitory effect of metformin on gluconeogenesis is mediated, at least in part, by upregulating SOCS2 and therefore reducing hepatic gluconeogenic genes expression. SOCS2 may represent a new therapeutic target for the treatment of diabetes.