AMPK regulates metabolic actions of glucocorticoids by phosphorylating the glucocorticoid receptor through p38 MAPK.
AMPK regulates metabolic actions of glucocorticoids by phosphorylating the glucocorticoid receptor through p38 MAPK.
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DOI：
10.1210/me.2010-0192
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发表时间：
2010-09
影响因子：
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通讯作者：
N. Nader;S. Ng;G. Lambrou;P. Pervanidou;Yonghong Wang;G. Chrousos;T. Kino
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文献类型：
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作者：
N. Nader;S. Ng;G. Lambrou;P. Pervanidou;Yonghong Wang;G. Chrousos;T. Kino
糖皮质激素通过将能量代谢转向分解代谢，在能量代谢的调节中发挥核心作用，而 AMP 激活蛋白激酶 (AMPK) 是能量稳态的主要调节器，感知能量消耗并刺激增加燃料摄取和节省外周供应的途径。我们在此表明，AMPK 通过靶向糖皮质激素受体 (GR) 并以组织和启动子特异性方式修改糖皮质激素反应基因的转录，从而调节糖皮质激素对碳水化合物代谢的作用。大鼠体内 AMPK 的激活可逆转糖皮质激素诱导的肝脂肪变性，并抑制糖皮质激素介导的葡萄糖代谢刺激。肝脏转录组分析表明 AMPK 和糖皮质激素信号通路之间存在明显重叠，主要从 AMPK 引导至糖皮质激素作用。 AMPK 通过磷酸化和随后激活 p38 MAPK 间接磷酸化人类 GR 的丝氨酸 211，并通过改变转录共调节因子对 DNA 结合的 GR 的吸引力来实现这一点。在人外周单核细胞中，AMPK mRNA 表达与糖皮质激素反应性糖皮质激素诱导亮氨酸拉链蛋白的表达呈正相关，后者也与受试者的体重指数呈正相关。这些结果表明 AMPK 介导的能量控制系统调节糖皮质激素在靶组织中的作用。由于糖皮质激素作用的增强与代谢紊乱的发生有关，因此 AMPK 的激活可能是开发针对这些病理的药物干预措施的有希望的目标。
Glucocorticoids play central roles in the regulation of energy metabolism by shifting it toward catabolism, whereas AMP-activated protein kinase (AMPK) is the master regulator of energy homeostasis, sensing energy depletion and stimulating pathways of increasing fuel uptake and saving on peripheral supplies. We showed here that AMPK regulates glucocorticoid actions on carbohydrate metabolism by targeting the glucocorticoid receptor (GR) and modifying transcription of glucocorticoid-responsive genes in a tissue- and promoter-specific fashion. Activation of AMPK in rats reversed glucocorticoid-induced hepatic steatosis and suppressed glucocorticoid-mediated stimulation of glucose metabolism. Transcriptomic analysis in the liver suggested marked overlaps between the AMPK and glucocorticoid signaling pathways directed mostly from AMPK to glucocorticoid actions. AMPK accomplishes this by phosphorylating serine 211 of the human GR indirectly through phosphorylation and consequent activation of p38 MAPK and by altering attraction of transcriptional coregulators to DNA-bound GR. In human peripheral mononuclear cells, AMPK mRNA expression positively correlated with that of glucocorticoid-responsive glucocorticoid-inducible leucine zipper protein, which correlated also positively with the body mass index of subjects. These results indicate that the AMPK-mediated energy control system modulates glucocorticoid action at target tissues. Because increased action of glucocorticoids is associated with the development of metabolic disorders, activation of AMPK could be a promising target for developing pharmacological interventions to these pathologies.