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Nature:禁食及糖尿病条件下肝糖异生的调节机制

来源:生物谷 2012-04-09 15:17

在禁食状态,体液中循环的胰高血糖素的增加通过诱导糖原异生作用,促进了肝脏葡萄糖的产生。促发cAMP信号通路,通过CREB辅激活因子CRTC2的去磷酸化,提升了糖原异生基因的表达。胰高血糖素在一定程度上通过蛋白激酶A(PKA)介导的对CRTC2激酶SIK2的抑制作用,促进了CRTC2的去磷酸化。

已知许多Ser/Thr磷酸酶似乎都能引起CRTC2的去磷酸化,但是通过哪种激素信号来调节这些酶还不可知。

近日,美国哥伦比亚大学的研究人员发现,老鼠的胰高血糖素通过动员细胞内的钙存储,激活钙/钙调蛋白依赖的Ser/Thr磷酸化酶(又称为PP3CA),促进了肝细胞中CRTC2的去磷酸化。胰高血糖素通过PKA介导的肌醇三磷酸受体(InsP3Rs)的磷酸化,提升了细胞质基质的钙浓度。激活的InsP3Rs促进了磷酸酶介导的CRCT2的去磷酸化作用,增强了糖原异生基因的表达。

在进食期间,胰岛素的表达增加,通过AKT介导的InsP3Rs的失活,降低了CRCT2的活性。而在糖尿病患者中,InsP3R的活性被提高,导致了糖原异生作用的上调。

在胰岛素抗性背景下,肝内InsP3Rs以及磷酸酶的下调提升了循环的葡萄糖的水平。这些结果阐明了在禁食及糖尿病InsP3Rs调节肝脏葡萄糖的机制。相关论文于4月8日在Nature上在线发表。(生物谷Deepblue编译)

Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes

Yiguo Wang,Gang Li,Jason Goode, Jose C. Paz, Kunfu Ouyang, Robert Screaton, Wolfgang H. Fischer, Ju Chen, Ira Tabas & Marc Montminy.

In the fasted state, increases in circulating glucagon promote hepatic glucose production through induction of the gluconeogenic program.Triggering of the cyclic AMP pathway increases gluconeogenic gene expression via the de-phosphorylation of the CREB co-activator CRTC2.Glucagon promotes CRTC2 dephosphorylation in part through the protein kinase A (PKA)-mediated inhibition of the CRTC2 kinase SIK2. A number of Ser/Thr phosphatases seem to be capable of dephosphorylating CRTC2, but the mechanisms by which hormonal cues regulate these enzymes remain unclear.Here we show in mice that glucagon stimulates CRTC2 dephosphorylation in hepatocytes by mobilizing intracellular calcium stores and activating the calcium/calmodulin-dependent Ser/Thr-phosphatase calcineurin (also known as PP3CA).Glucagon increased cytosolic calcium concentration through the PKA-mediated phosphorylation of inositol-1,4,5-trisphosphate receptors (InsP3Rs), which associate with CRTC2. After their activation, InsP3Rs enhanced gluconeogenic gene expression by promoting the calcineurin-mediated dephosphorylation of CRTC2.During feeding, increases in insulin signalling reduced CRTC2 activity via the AKT-mediated inactivation of InsP3Rs. InsP3R activity was increased in diabetes, leading to upregulation of the gluconeogenic program.As hepatic downregulation of InsP3Rs and calcineurin improved circulating glucose levels in insulin resistance, these results demonstrate how interactions between cAMP and calcium pathways at the level of the InsP3R modulate hepatic glucose production under fasting conditions and in diabetes.

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