Hunting for the SNARK in metabolic disease
Hunting for the SNARK in metabolic disease
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DOI：
10.1152/ajpendo.00178.2009
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发表时间：
2009-05-01
影响因子：
5.1
通讯作者：
Zierath, Juleen R.
中科院分区：
文献类型：
--
作者：
Egan, Brendan;Zierath, Juleen R.
能量平衡失调是肥胖和2型糖尿病病因学的主要组成部分，表现为多种组织（包括脑、肝和骨骼肌）中代谢稳态改变和胰岛素抵抗。AMP活化蛋白激酶（AMPK）是一种进化上保守的丝氨酸/苏氨酸激酶，在细胞水平上充当能量平衡的主传感器和调节器（8，31），其发现对我们理解全身能量稳态至关重要。调节各种代谢组织中的AMPK活性是治疗策略的一个特征，如运动（1）和二甲双胍（27），已知可改善2型糖尿病和胰岛素抵抗的代谢稳态。AMPK的代谢调节作用已被广泛研究，但对AMPK相关激酶在代谢调节中的作用知之甚少。人激酶组中的12种蛋白激酶（BRSK 1、BRSK 2、NUAK 1、NUAK 2、QIK、QSK、SIK、MARK 1、MARK 2、MARK 3、MARK 4和MELK）与AMPK 1和AMPK 2密切相关（18），因此形成称为“AMPK相关激酶”的14种激酶系统发生树（图1A）。在本期杂志中，Ichinoseki-Sekine et al. (9)已经探索了NUAK 2，也称为SNARK [SNF（蔗糖，非发酵）1/AMPK相关激酶）]在久坐和体力活动动物的全身能量稳态中的作用。他们提供了证据证明半等位基因Snark缺陷对全身代谢有强大的影响（图1B），表明这种AMPK相关激酶是以前未被认识的全身代谢调节剂。AMPK的结构、调节和代谢作用的全面综述已在其他地方发表（8，17，31）;本文简要讨论了一些方面。AMPK最初被鉴定为负责5-AMP对HMG-CoA还原酶和乙酰辅酶A羧化酶活性的抑制作用的激酶（3），尽管早期的工作者已经将AMP传感牵涉到细胞代谢中（5，33）。大量消耗ATP（如代谢毒物）或增加细胞AMP/ATP比率（如葡萄糖剥夺或肌肉收缩）的细胞应激激活AMPK（8）。因此，AMPK作为细胞代谢的主要调节剂，响应细胞中能量电荷的变化（8）。AMPK激活的一般效应以这样的方式发生，即通过抑制生物合成途径和合成代谢途径来保存ATP，同时刺激分解代谢途径，该途径在控制机制中产生ATP，该机制用于恢复细胞能量（ATP）储存（8）。在骨骼肌中，观察到AMPK对糖原合成（11）和蛋白质合成（2）的抑制作用以及对葡萄糖转运（19）和脂肪酸氧化（28）的允许作用。慢性或组成性AMPK的影响
DYSREGULATION OF ENERGY BALANCE is a primary constituent in the etiology of obesity and type 2 diabetes mellitus, which is manifested by altered metabolic homeostasis and insulin resistance in a variety of tissues, including brain, liver, and skeletal muscle. The discovery of the AMP-activated protein kinase (AMPK), an evolutionarily conserved serine/threonine kinase that acts a master sensor and regulator of energy balance at the cellular level (8, 31), has been critical to our understanding of whole body energy homeostasis. Modulation of AMPK activity in various metabolic tissues is a feature of therapeutic strategies, such as exercise (1) and metformin (27), known to improve metabolic homeostasis in type 2 diabetes and insulin resistance. Metabolic regulation by AMPK has been extensively studied, but little is known of the role of AMPK-related kinases in metabolic regulation. Twelve protein kinases (BRSK1, BRSK2, NUAK1, NUAK2, QIK, QSK, SIK, MARK1, MARK2, MARK3, MARK4 and MELK) in the human kinome are closely related to AMPK1 and AMPK2 (18), thus forming a 14 kinase phylogenetic tree known as “AMPK-related kinases”(Fig. 1A). In this issue of the Journal, Ichinoseki-Sekine et al.(9) have explored the role of NUAK2, also known as SNARK [SNF (sucrose, nonfermenting) 1/AMPK-related kinase)], in whole body energy homeostasis in sedentary and physically active animals. They provide evidence for a robust effect on whole body metabolism by hemiallelic Snark deficiency (Fig. 1B), suggesting that this AMPK-related kinase is a previously unrecognized regulator of whole-body metabolism.Thorough reviews of the structure, regulation, and metabolic effects of AMPK have been published elsewhere (8, 17, 31); some aspects are briefly discussed here. AMPK was originally identified as a kinase responsible for inhibitory effects of 5-AMP on both HMG-CoA reductase and acetyl-CoA carboxylase activity (3), although earlier workers had implicated AMP sensing in cellular metabolism (5, 33). A wide range of cellular stresses that deplete ATP (such as metabolic poisons) or increase the cellular AMP/ATP ratio (such as glucose deprivation or muscle contraction) activate AMPK (8). Consequently, AMPK acts as a master regulator of cellular metabolism in response to alterations in energy charge in the cell (8). The generalized effects of AMPK activation occur in such a manner as to conserve ATP by inhibiting biosynthetic pathways and anabolic pathways while stimulating catabolic pathways that generate ATP in a control mechanism that acts to restore cellular energy (ATP) stores (8). In the context of skeletal muscle, this is observed acutely as a suppressive effect of AMPK on glycogen synthesis (11) and protein synthesis (2) and a permissive effect on glucose transport (19) and fatty acid oxidation (28). The effects of chronic or constitutive AMPK