A kinome screen reveals that Nemo-like kinase is a key suppressor of hepatic gluconeogenesis
A kinome screen reveals that Nemo-like kinase is a key suppressor of hepatic gluconeogenesis
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激酶组筛选揭示 Nemo 样激酶是肝糖异生的关键抑制剂
DOI：
10.1016/j.cmet.2021.04.006
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发表时间：
2021-06-01
期刊：
影响因子：
29
通讯作者：
Li, Hongliang
中科院分区：
文献类型：
--
作者：
Ji, Yan-Xiao;Wang, Yutao;Li, Hongliang
抗高血糖治疗是2型糖尿病（T2D）治疗的重要优先事项。肝葡萄糖生成过多（HGP）是空腹高血糖的主要原因。因此，更好地了解它的调节将是重要的，以开发有效的抗高血糖治疗。使用靶向HGP的激酶组筛选方法结合转录组分析，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CRTC2和FOXO 1（肝再生的两种关键调节因子）的核输出，导致前者的蛋白酶体依赖性降解和后者的自我转录活性和表达的抑制。重要的是，NLK的表达在患有糖尿病的个体和糖尿病啮齿动物模型的肝脏中下调，并且在小鼠模型中恢复NLK表达改善高血糖症。因此，我们的研究结果揭示了NLK是致炎调控网络中的关键参与者，也是T2D的潜在治疗靶点。
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 proteasomedependent 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.