Suppressor of MEK null (SMEK)/protein phosphatase 4 catalytic subunit (PP4C) is a key regulator of hepatic gluconeogenesis
Suppressor of MEK null (SMEK)/protein phosphatase 4 catalytic subunit (PP4C) is a key regulator of hepatic gluconeogenesis
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DOI：
10.1073/pnas.1012665107
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发表时间：
2010-10-12
影响因子：
11.1
通讯作者：
Koo, Seung-Hoi
中科院分区：
文献类型：
--
作者：
Yoon, Young-Sil;Lee, Min-Woo;Koo, Seung-Hoi
禁食促进肝脏再生以维持葡萄糖稳态。cAMP反应元件结合蛋白（CREB）调节的转录共激活因子2（CRTC 2）负责促性腺激素基因的转录激活，并且对于在肝脏中传递胰高血糖素和胰岛素的相反激素信号至关重要。在这里，我们表明，抑制MEK null 1（SMEK 1）和SMEK 2 [蛋白磷酸酶4（PP 4）调节亚基3a和3b，分别]直接参与小鼠肝脏葡萄糖代谢的调节。肝脏SMEK 1/2的表达在禁食期间或在胰岛素抵抗状况的小鼠模型中以过氧化物酶体增殖物激活受体-γ辅激活因子1 α（PGC-1 α）依赖性方式上调。SMEK的过表达促进血糖升高，同时增加肝细胞癌基因的表达，而SMEK蛋白的缺失降低高血糖并增强CRTC 2磷酸化; S171 A CRTC 2对盐诱导激酶（SIK）依赖性抑制无效，从而减弱了该作用。综上所述，我们认为哺乳动物SMEK/PP 4C蛋白通过CRTC 2的去磷酸化参与肝脏葡萄糖代谢的调节。
Fasting promotes hepatic gluconeogenesis to maintain glucose homeostasis. The cAMP-response element binding protein (CREB)regulated transcriptional coactivator 2 (CRTC2) is responsible for transcriptional activation of gluconeogenic genes and is critical for conveying the opposing hormonal signals of glucagon and insulin in the liver. Here, we show that suppressor of MEK null 1 (SMEK1) and SMEK2 [protein phosphatase 4 (PP4) regulatory sub-units 3a and 3b, respectively] are directly involved in the regulation of hepatic glucose metabolism in mice. Expression of hepatic SMEK1/2 is up-regulated during fasting or in mouse models of insulin- resistant conditions in a Peroxisome Proliferator-Activated Receptor-gamma Coactivator 1 alpha (PGC-1 alpha)-dependent manner. Overexpression of SMEK promotes elevations in plasma glucose with increased hepatic gluconeogenic gene expression, whereas depletion of the SMEK proteins reduces hyperglycemia and enhances CRTC2 phosphorylation; the effect is blunted by S171A CRTC2, which is refractory to salt-inducible kinase (SIK)-dependent inhibition. Taken together, we would propose that mammalian SMEK/PP4C proteins are involved in the regulation of hepatic glucose metabolism through dephosphorylation of CRTC2.