Ji Yan-Xiao, Wang Yutao, Li Peng-Long, Cai Lin, Wang Xiao-Ming, Bai Lan, Liu Zhen, Tian Han, Tian Song, Zhang Peng, Zhang Xiao-Jing, Cheng Xu, Yuan Yufeng, She Zhi-Gang, Hu Yufeng, Li Hongliang
Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital, School of Basic Medical Sciences, Wuhan University, Wuhan, China; Institute of Model Animal of Wuhan University, Wuhan, China; Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
Institute of Model Animal of Wuhan University, Wuhan, China; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
Cell Metab. 2021 Jun 1;33(6):1171-1186.e9. doi: 10.1016/j.cmet.2021.04.006. Epub 2021 May 4.
Antihyperglycemic therapy is an important priority for the treatment of type 2 diabetes (T2D). Excessive hepatic glucose production (HGP) is a major cause of fasting hyperglycemia. Therefore, a better understanding of its regulation would be important to develop effective antihyperglycemic therapies. Using a gluconeogenesis-targeted kinome screening approach combined with transcriptome analyses, we uncovered Nemo-like kinase (NLK) as a potent suppressor of HGP. Mechanistically, NLK phosphorylates and promotes nuclear export of CRTC2 and FOXO1, two key regulators of hepatic gluconeogenesis, resulting in the proteasome-dependent degradation of the former and the inhibition of the self-transcriptional activity and expression of the latter. Importantly, the expression of NLK is downregulated in the liver of individuals with diabetes and in diabetic rodent models and restoring NLK expression in the mouse model ameliorates hyperglycemia. Therefore, our findings uncover NLK as a critical player in the gluconeogenic regulatory network and as a potential therapeutic target for T2D.
抗高血糖治疗是2型糖尿病（T2D）治疗的重要优先事项。肝脏葡萄糖生成过多（HGP）是空腹血糖过高的主要原因。因此，更好地了解其调节机制对于开发有效的抗高血糖治疗方法至关重要。通过使用针对糖异生的激酶组筛选方法并结合转录组分析，我们发现Nemo样激酶（NLK）是HGP的有效抑制剂。从机制上讲，NLK磷酸化并促进肝脏糖异生的两个关键调节因子CRTC2和FOXO1的核输出，导致前者通过蛋白酶体依赖性降解，后者的自我转录活性和表达受到抑制。重要的是，在糖尿病患者的肝脏和糖尿病啮齿动物模型中，NLK的表达下调，在小鼠模型中恢复NLK表达可改善高血糖症。因此，我们的研究结果揭示NLK是糖异生调节网络中的关键参与者，也是T2D的潜在治疗靶点。
