AMPK signaling

AMPK signaling pathway, a fuel sensor and regulator, promotes ATP-producing and inhibits ATP-consuming pathways in various tissues. AMPK is a heterotrimer composed of alpha-catalytic and beta and gamma-regulatory subunits. Humans and rodents have two alpha and beta and three gamma isoforms; some genes are subject to alternative splicing increasing the range of possible heterotrimer combinations. Cellular stresses that inhibit ATP production or increase its consumption change the AMP:ATP ratio and activate the pathway. AMPK activation by AMP is not completely understood; the current model states that binding of AMP to the gamma subunit leads to conformational changes that allosterically activate AMPK and render phosphorylated-Thr172 unavailable for inhibitory dephosphorylation. ATP antagonizes the effect of AMP; both AMP and ATP bind in a mutually exclusive manner to the Bateman (CBS) domains of the gamma subunit. The upstream kinase, known as Lkb1, is a complex of one catalytic and two regulatory subunits; Lkb1 is believed to be 'constitutively active'. In certain cell types, Thr172 can be phosphorylated by calmodulin-dependent protein kinase kinases (CAmKK), in turn activated by calcium. A well known role of AMPK is in the regulation of lipid metabolism; it stimulates fatty acids oxidation and inhibits their synthesis. Phosphorylation by AMPK inhibits acetyl-CoA carboxylase (ACC) and results in reduced levels of malonyl-CoA product. Malonyl CoA is a substrate in the de novo synthesis of fatty acids and fatty acids elongation. Importantly, it is also an inhibitor of the carnitine palmitoyl transferase I, required for the transfer of primed cytosolic fatty acids into the mitochondrion where they can undergo degradative beta-oxidation. AMPK inhibits mTOR signaling pathway by activating Tsc2 and downstream of Tsc2 by inhibiting Raptor component of mTOR complex 1 [note that this effect is opposite to Tsc2 phosphorylation and inactivation by PI3K-Akt signaling downstream of insulin]. AMPK is also involved in promoting glucose uptake and utilization and integrates adipokynes and hormonal signals in both the hypothalamus and the periphery with potential impact on energy expenditure and uptake by molecular mechanisms that remain to be established. Due to its roles in fuel regulation, the AMPK pathway is regarded as a potential therapeutic target for diabetes type II, obesity and metabolic syndrome. As a note, drugs used in the treatment of insulin resistance and diabetes can activate AMPK. AMP-activated protein kinase (AMPK) plays a key role as a master regulator of cellular energy homeostasis. The kinase is activated in response to stresses that deplete cellular ATP supplies such as low glucose, hypoxia, ischemia and heat shock. It exists as a heterotrimeric complex composed of a catalytic α subunit and regulatory β and γ subunits. Binding of AMP to the γ subunit allosterically activates the complex, making it a more attractive substrate for its major upstream AMPK kinase, LKB1. Several studies indicate that signaling through adiponectin, leptin and CAMKKβ may also be important in activating AMPK. As a cellular energy sensor responding to low ATP levels, AMPK activation positively regulates signaling pathways that replenish cellular ATP supplies. For example, activation of AMPK enhances both the transcription and translocation of GLUT4, resulting in an increase in insulin-stimulated glucose uptake. In addition, it also stimulates catabolic processes such as fatty acid oxidation and glycolysis via inhibition of ACC and activation of PFK2. AMPK negatively regulates several proteins central to ATP consuming processes such as TORC2, glycogen synthase, SREBP-1 and TSC2, resulting in the downregulation or inhibition of gluconeogenesis, glycogen, lipid and protein synthesis. Due to its role as a central regulator of both lipid and glucose metabolism, AMPK is considered to be a key therapeutic target for the treatment of obesity, type II diabetes mellitus, and cancer.

AMPK信号通路，作为一种燃料传感器和调节因子，在各种组织中促进ATP的产生并抑制ATP的消耗途径。AMPK由α催化亚基和β、γ调节亚基组成的异源三聚体。人类和啮齿动物具有两种α、β和三种γ同种异构体；某些基因受到选择性剪接的影响，增加了可能异源三聚体组合的范围。抑制ATP产生或增加其消耗的细胞应激会改变AMP:ATP的比例并激活该通路。AMP通过AMPK激活的机制尚不完全清楚；当前模型表明，AMP与γ亚基的结合导致构象变化，通过变构激活AMPK并使磷酸化的Thr172对抑制性去磷酸化不可用。ATP对抗AMP的效果；AMP和ATP以互斥的方式结合到γ亚基的Bateman（CBS）结构域。上游激酶Lkb1由一个催化亚基和两个调节亚基组成；Lkb1被认为具有‘组成性活性’。在某些细胞类型中，Thr172可被钙调蛋白依赖性蛋白激酶激酶（CAmKK）磷酸化，而CAmKK则由钙激活。AMPK在调节脂质代谢方面的作用众所周知；它刺激脂肪酸的氧化并抑制其合成。AMPK的磷酸化抑制乙酰辅酶A羧化酶（ACC），导致丙二酰辅酶A产物水平降低。丙二酰辅酶A是脂肪酸从头合成和脂肪酸延长的底物。重要的是，它还是肉碱棕榈酰转移酶I的抑制剂，该酶对于将预处理的细胞质脂肪酸转运到线粒体中进行降解性β-氧化是必需的。AMPK通过激活Tsc2和抑制mTOR复合体1中的Raptor成分来抑制mTOR信号通路，这一效应与胰岛素下游PI3K-Akt信号通路通过Tsc2磷酸化和失活的作用相反。AMPK还参与促进葡萄糖的摄取和利用，并在下丘脑和周围组织中整合脂肪因子和激素信号，可能通过尚待建立的分子机制影响能量消耗和摄取。由于其燃料调节的作用，AMPK通路被视为II型糖尿病、肥胖和代谢综合征的潜在治疗靶点。值得注意的是，用于治疗胰岛素抵抗和糖尿病的药物可以激活AMPK。AMP激活的蛋白激酶（AMPK）作为细胞能量稳态的主导调节因子，发挥着关键作用。激酶在应对低葡萄糖、缺氧、缺血和热应激等耗竭细胞ATP供应的应激时被激活。它以由催化α亚基和调节β、γ亚基组成的异源三聚体形式存在。AMP与γ亚基的结合通过变构激活复合物，使其成为其主要上游AMPK激酶LKB1的更吸引人的底物。几项研究表明，通过脂联素、瘦素和CAMKKβ的信号传导也可能在激活AMPK中发挥重要作用。作为对低ATP水平做出反应的细胞能量传感器，AMPK的激活正向调节补充细胞ATP供应的信号通路。例如，AMPK的激活增强了GLUT4的转录和转位，从而增加了胰岛素刺激的葡萄糖摄取。此外，它还通过抑制ACC和激活PFK2来刺激分解代谢过程，如脂肪酸氧化和糖酵解。AMPK负向调节几个与ATP消耗过程相关的中心蛋白质，如TORC2、糖原合成酶、SREBP-1和TSC2，导致糖异生、糖原、脂质和蛋白质合成的下调或抑制。由于其作为脂质和葡萄糖代谢的中心调节因子的作用，AMPK被认为是治疗肥胖、II型糖尿病和癌症的关键治疗靶点。