AICAR positively regulate glycogen synthase activity and LDL receptor expression through Raf-1/MEK/p42/44MAPK/p90RSK/GSK-3 signaling cascade.
AICAR positively regulate glycogen synthase activity and LDL receptor expression through Raf-1/MEK/p42/44MAPK/p90RSK/GSK-3 signaling cascade.
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DOI：
10.1016/j.bcp.2007.08.028
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发表时间：
2008-01
影响因子：
5.8
通讯作者：
Hsiang-Ming Wang;S. Mehta;R. Bansode;Wei Huang;K. Mehta
中科院分区：
文献类型：
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作者：
Hsiang-Ming Wang;S. Mehta;R. Bansode;Wei Huang;K. Mehta
5-氨基咪唑-4-甲酰胺-1-β-d-呋喃核糖苷（AICAR）是一种常用的药理学试剂，用于研究类似于运动的生理效应。然而，AICAR在肝脏中发挥下游作用的信号转导途径知之甚少。我们在此报告AICAR不仅激活AMPK，而且在人肝癌HepG 2细胞中以时间依赖性方式磷酸化/失活糖原合成酶激酶-3 α/β（GSK-3α/β）和去磷酸化/激活糖原合成酶（GS）。AICAR和GSK-3之间的信号连接是间接的，并且涉及Raf-1/MEK/p42/44 MAPK/p90 RSK信号级联的激活，因为MEK的药理学抑制显著降低GSK-3的磷酸化/失活以及随后的GS的去磷酸化/激活。此外，沉默p42/44 MAPK的底物p90 RSK的表达，减弱AICAR依赖性GSK-3磷酸化，暗示该激酶是AICAR信号传导至GSK-3的关键介质。此外，与Raf-1激酶级联反应的参与一致，AICAR以p42/44 MAPK依赖的方式诱导低密度脂蛋白（LDL）受体表达。最后，AICAR需要AMPK-α2依赖性和非依赖性途径来激活Raf-1激酶级联，因为AMPKα2活性的抑制而不是AMPKα1，部分阻断AICAR依赖性p42/44 MAPK激活和GSK-3磷酸化/失活。总的来说，这些结果突出了Raf-1信号级联作为AICAR作用于HepG 2细胞中葡萄糖和脂质代谢的关键介质。
5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) is a commonly used pharmacological agent to study physiological effects which are similar to those of exercise. However, signal transduction pathways by which AICAR elicits downstream effects in liver are poorly understood. We report here that AICAR not only activated AMPK but also phosphorylated/deactivated glycogen synthase kinase-3 alpha/beta (GSK-3α/β) and dephophorylated/activated glycogen synthase (GS) in a time-dependent manner in human hepatoma HepG2 cells. The signal connection between AICAR and GSK-3 is indirect and involves activation of Raf-1/MEK/p42/44MAPK/p90RSKsignaling cascade as pharmacologic inhibition of MEK significantly reduced phosphorylation/deactivation of GSK-3 and consequent dephosphorylation/activation of GS. Moreover, silencing the expression of p90RSK, a substrate of p42/44MAPK, attenuated AICAR-dependent GSK-3 phosphorylation, implicating this kinase as a key mediator of AICAR signaling to GSK-3. Furthermore, consistent with the involvement of Raf-1 kinase cascade, AICAR-induced low-density lipoprotein (LDL) receptor expression in a p42/44MAPK-dependent manner. Finally, AICAR requires AMPK-α2-dependent and -independent pathways to activate Raf-1 kinase cascade as suppression of AMPKα2 activity, and not of AMPKα1, partially blocked AICAR-dependent p42/44MAPKactivation and GSK-3 phosphorylation/deactivation. Collectively, these results highlight Raf-1 signaling cascade as the critical mediator of AICAR action on glucose and lipid metabolism in HepG2 cells.