The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver.
The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver.
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DOI：
10.1038/ncomms5535
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发表时间：
2014-08-04
影响因子：
16.6
通讯作者：
Sakamoto, Kei
中科院分区：
文献类型：
--
作者：
Patel, Kashyap;Foretz, Marc;Marion, Allison;Campbell, David G.;Gourlay, Robert;Boudaba, Nadia;Tournier, Emilie;Titchenell, Paul;Peggie, Mark;Deak, Maria;Wan, Min;Kaestner, Klaus H.;Goransson, Olga;Viollet, Benoit;Gray, Nathanael S.;Birnbaum, Morris J.;Sutherland, Calum;Sakamoto, Kei
LKB 1是一种主要激酶，通过腺苷一磷酸激活蛋白激酶（AMPK）和其他12种密切相关的激酶调节代谢和生长。LKB 1的肝脏特异性消融导致体外肝细胞中葡萄糖产生增加和体内禁食小鼠中高血糖症。在这里，我们报告的盐诱导激酶（SIK 1，2和3），AMPK相关激酶家族的成员，发挥关键作用，作为LKB 1下游的肝脏中的促血管生成抑制剂。选择性SIK抑制剂HG-9-91-01促进转录共激活因子CRTC 2/3的去磷酸化，导致肝细胞中促凋亡基因表达和葡萄糖产生增强，当引入HG-9-91-01不敏感突变体SIK或消融LKB 1时，该效应被消除。虽然SIK 2被认为是胰岛素介导的抑制新生血管生成的关键调节因子，但我们提供的遗传证据表明，肝脏特异性消融SIK 2对新生血管生成没有影响，胰岛素不调节SIK 2磷酸化或活性。总的来说，我们证明了LKB 1-SIK通路在肝脏中作为一个关键的致炎性看门人发挥作用。 肝脏是葡萄糖稳态的重要调节器。在这里，作者通过显示SIK蛋白激酶抑制肝再生，胰高血糖素而不是胰岛素调节SIK 2的磷酸化，提供了对控制肝再生的分子信号通路的深入了解。
LKB1 is a master kinase that regulates metabolism and growth through adenosine monophosphate-activated protein kinase (AMPK) and 12 other closely related kinases. Liver-specific ablation of LKB1 causes increased glucose production in hepatocytes in vitro and hyperglycaemia in fasting mice in vivo. Here we report that the salt-inducible kinases (SIK1, 2 and 3), members of the AMPK-related kinase family, play a key role as gluconeogenic suppressors downstream of LKB1 in the liver. The selective SIK inhibitor HG-9-91-01 promotes dephosphorylation of transcriptional co-activators CRTC2/3 resulting in enhanced gluconeogenic gene expression and glucose production in hepatocytes, an effect that is abolished when an HG-9-91-01-insensitive mutant SIK is introduced or LKB1 is ablated. Although SIK2 was proposed as a key regulator of insulin-mediated suppression of gluconeogenesis, we provide genetic evidence that liver-specific ablation of SIK2 alone has no effect on gluconeogenesis and insulin does not modulate SIK2 phosphorylation or activity. Collectively, we demonstrate that the LKB1–SIK pathway functions as a key gluconeogenic gatekeeper in the liver. The liver is an important regulator of glucose homeostasis. Here, the authors provide insight into the molecular signalling pathways controlling hepatic gluconeogenesis by showing that SIK protein kinases suppress gluconeogenesis, and that glucagon—but not insulin—regulates phosphorylation of SIK2.
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影响因子：
8.2
作者：
Rena, Graham;Pearson, Ewan R.;Sakamoto, Kei
通讯作者：
Sakamoto, Kei
影响因子：
29
作者：
Le Lay J;Tuteja G;White P;Dhir R;Ahima R;Kaestner KH
通讯作者：
Kaestner KH
DOI：
10.1038/nrm3072
发表时间：
2011-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
29
作者：
Lin HV;Accili D
通讯作者：
Accili D
影响因子：
14.8
作者：
Luo, Jinyong;Deng, Zhong-Liang;He, Tong-Chuan
通讯作者：
He, Tong-Chuan