Viollet B, Mounier R, Leclerc J, Yazigi A, Foretz M, Andreelli F
Département endocrinologie, métabolisme et cancer, institut Cochin, université Paris-Descartes, CNRS (UMR 8104), and Inserm, U567, Paris, France.
Diabetes Metab. 2007 Dec;33(6):395-402. doi: 10.1016/j.diabet.2007.10.004. Epub 2007 Nov 7.
In the light of recent studies in humans and rodents, AMP-activated protein kinase (AMPK), a phylogenetically conserved serine/threonine protein kinase, has been described as an integrator of regulatory signals monitoring systemic and cellular energy status. AMP-activated protein kinase (AMPK) has been proposed to function as a 'fuel gauge' to monitor cellular energy status in response to nutritional environmental variations. Recently, it has been proposed that AMPK could provide a link in metabolic defects underlying progression to the metabolic syndrome. AMPK is a heterotrimeric enzyme complex consisting of a catalytic subunit alpha and two regulatory subunits beta and gamma. AMPK is activated by rising AMP and falling ATP. AMP activates the system by binding to the gamma subunit that triggers phosphorylation of the catalytic alpha subunit by the upstream kinases LKB1 and CaMKKbeta (calmodulin-dependent protein kinase kinase). AMPK system is a regulator of energy balance that, once activated by low energy status, switches on ATP-producing catabolic pathways (such as fatty acid oxidation and glycolysis), and switches off ATP-consuming anabolic pathways (such as lipogenesis), both by short-term effect on phosphorylation of regulatory proteins and by long-term effect on gene expression. As well as acting at the level of the individual cell, the system also regulates food intake and energy expenditure at the whole body level, in particular by mediating the effects of insulin sensitizing adipokines leptin and adiponectin. AMPK is robustly activated during skeletal muscle contraction and myocardial ischaemia playing a role in glucose transport and fatty acid oxidation. In liver, activation of AMPK results in enhanced fatty acid oxidation as well as decreased glucose production. Moreover, the AMPK system is one of the probable targets for the anti-diabetic drugs biguanides and thiazolidinediones. Thus, the relationship between AMPK activation and beneficial metabolic effects provide the rationale for the development of new therapeutic strategies in metabolic disorders.
根据最近在人类和啮齿动物中的研究，AMP激活的蛋白激酶（AMPK）是一种系统发育上保守的丝氨酸/苏氨酸蛋白激酶，被描述为监测全身和细胞能量状态的调节信号整合器。有人提出，AMP激活的蛋白激酶（AMPK）可作为一种“燃料表”，以响应营养环境变化来监测细胞能量状态。最近，有人提出AMPK可能在代谢综合征进展所潜在的代谢缺陷中起到关联作用。AMPK是一种异源三聚体酶复合物，由一个催化亚基α和两个调节亚基β和γ组成。AMPK通过AMP升高和ATP降低而被激活。AMP通过与γ亚基结合来激活该系统，γ亚基会触发上游激酶LKB1和CaMKKβ（钙调蛋白依赖性蛋白激酶激酶）对催化性α亚基的磷酸化。AMPK系统是能量平衡的调节剂，一旦被低能量状态激活，就会开启产生ATP的分解代谢途径（如脂肪酸氧化和糖酵解），并关闭消耗ATP的合成代谢途径（如脂肪生成），这是通过对调节蛋白磷酸化的短期作用以及对基因表达的长期作用来实现的。该系统不仅在单个细胞水平发挥作用，还在全身水平调节食物摄入和能量消耗，特别是通过介导胰岛素增敏脂肪因子瘦素和脂联素的作用。在骨骼肌收缩和心肌缺血期间，AMPK会被强烈激活，在葡萄糖转运和脂肪酸氧化中发挥作用。在肝脏中，AMPK的激活会导致脂肪酸氧化增强以及葡萄糖生成减少。此外，AMPK系统是抗糖尿病药物双胍类和噻唑烷二酮类药物可能的靶点之一。因此，AMPK激活与有益代谢效应之间的关系为开发治疗代谢紊乱的新治疗策略提供了理论依据。
