腺苷酸活化蛋白激酶与心血管疾病

1973年,Gobson和Carlson分别报道了腺苷酸活化蛋白激酶(adenosine monophosphate-activated protein kinase,AMPK)广泛存在真核细胞生物中,通过影响细胞物质代谢的多个环节来维持细胞能量供求平衡和调节细胞功能.细胞能量不足时会激活AMPK,一方面抑制糖原、脂肪和胆固醇的合成,减少ATP的利用;另一方面,促进脂肪酸氧化、葡萄糖转运等,增加ATP的产生.反之,当细胞内存在高浓度的ATP则可以抑制该效应.……     

腺苷酸活化蛋白激酶与胰岛素抵抗

哺乳动物组织中，腺苷酸活化蛋白激酶（AMPK）是细胞内重要的能量代谢感受器，属于代谢敏感性蛋白激酶家族。它是调节多种代谢过程的重要信号分子，对于糖脂代谢尤有积极的调节作用。有证据表明，在抗糖尿病药物中，二甲双胍和噻唑烷二酮类药物均是通过激活AMPK而发挥胰岛素增敏作用的。     

腺苷酸活化蛋白激酶与肥胖的研究进展

肥胖已成为危险人类健康的常见的慢性疾病,但目前尚无有效的治疗手段.腺苷酸活化蛋白激酶是一种重要的代谢应激蛋白激酶,在全身的能量平衡中起关键性作用.在外周组织中,腺苷酸活化蛋白激酶影响多种代谢途径有利于正常细胞能量平衡的建立.腺苷酸活化蛋白激酶同样表达在下丘脑神经元中,下丘脑是调节能量平衡的关键中枢.近来研究证实,下丘脑腺苷酸活化蛋白激酶是一个重要的信号传导分子,它可以整合营养和激素信号、调节摄食行为和能量代谢.因此,通过对体重调节通路的深入了解,将促进用来开发治疗肥胖新药的新的分子靶点发现.     

腺苷酸活化蛋白激酶与胰岛素抵抗

腺苷酸活化蛋白激酶（AMP-activated protein kinase, AMPK）是一类重要的蛋白激酶,通过改变细胞代谢和调节基因转录恢复细胞ATP水平。AMPK参与了肌肉收缩介导的葡萄糖转运和脂肪酸氧化,抑制肝脏葡萄糖、胆固醇和甘油三酯产生,并具有调节食物摄取和体重的作用。AMPK信号通路是目前具有吸引力的治疗肥胖、胰岛素抵抗、2型糖尿病和其它代谢病的药理靶点。     

下丘脑的食欲调节网络

下丘脑是食欲调节的中枢,其内存在“食欲调节网络”：内侧下丘脑区的弓状核,腹内侧核,背内侧核,室旁核,视交叉上核和外侧下丘脑区均是“网络中心”;其间传递的“文件”是食欲调节因子;各种因子的受体是位于网络中心的“接收装置”。     

下丘脑的食欲调节网络

下丘脑是食欲调节的中枢,其内存在“食欲调节网络”：内侧下丘脑区的弓状核、腹内侧核、背内侧核、室旁核、视交叉上核和外侧下丘脑区均是“网络中心”;其间传递的“文件”（ 内含食欲信息） 是食欲调节因子（ 包括多种食欲促进因子和抑制因子） ;各种因子的受体是位于网络中心的“接收装置”。下丘脑“食欲调节网络”是一个精细的食欲调节环路,如果打破其中任何一个单元的信息平衡,皆有可能破坏机体内的自身能量稳定,从而导致食欲亢进或厌食。     

腺苷酸活化蛋白激酶与心肌缺血再灌注损伤

心肌缺血再灌注损伤（MIRI）是指缺血期处于可逆损伤的心肌细胞恢复血液供应后产生更为严重的损伤,主要包括炎症反应、内皮细胞损伤、血流障碍、心肌细胞坏死和凋亡所致心肌梗死面积的扩大、再灌注心律失常、心肌顿抑及冠状微循环障碍等病理生理变化.腺苷酸活化蛋白激酶（5-adenosine monophosphate activated kinase,AMPK）通过调节多种代谢途径控制着心脏能量的供求平衡.AMPK不仅控制葡萄糖和脂类的摄入、储存和利用,还能调节多种代谢酶的活性以及离子通道的开放和相关基因的表达[1].AMPK还能够调节缺血再灌注过程中心肌能量代谢,降低缺血性损伤和心肌凋亡.因此,AMPK被认为是能量应激下心肌细胞代谢调节的关键激酶.     

腺苷酸活化蛋白激酶对糖脂代谢的影响

腺苷酸活化蛋白激酶 (AMPK)是一种重要的代谢应激蛋白激酶 ,在运动、缺氧等应激条件下可被高浓度的腺苷酸别构激活 ,AMPK一旦活化就可以使许多参与葡萄糖摄取和脂肪酸氧化的蛋白磷酸化 ,促进葡萄糖摄取 ,增加脂肪酸氧化 ,增加能量消耗 ,并且可以调控葡萄糖诱导基因的转录。 5 氨基 4 甲酰胺咪唑核糖核苷酸 (AICAR)是AMPK的非特异性激动剂 ,运动的急性效应 (增加骨骼肌葡萄糖摄取 )和慢性效应 (增加葡萄糖转运子 4 )都可以被AICAR所重复。AMPK可能在 2型糖尿病的运动治疗中发挥了重要作用。     

腺苷酸活化蛋白激酶对糖脂代谢的影响

腺苷酸活化蛋白激酶（AMPK）是一种重要的代谢应激蛋白激酶，在运动、缺氧等应激条件下可被高浓度的腺苷酸别构激活，AMPK一旦活化就可以使许多参与葡萄糖摄取和脂肪酸氧化的蛋白磷酸化，促进葡萄糖摄取，增加脂肪酸氧化，增加能量消耗，并且可以调控葡萄糖诱导基因的转录。5-氨基-4-甲酰胺噗唑核糖核苷酸（AICAR）是AMPK的非特异性激动剂，运动的急性效应（增加骨骼肌葡萄糖撮取）和慢性效应（增加葡萄糖转运子4）都可以被AICAR所重复。AMPK可能在2型糖尿病的运动治疗中发挥了重要作用。     

卒中后腺苷酸活化蛋白激酶作用的研究进展

腺苷酸活化蛋白激酶(adenosine monophosphate-activated protein kinase,AMPK)是一种代谢和应激反应的感受器和效应器,在调节能量代谢和维持机体稳态中,发挥着重要的作用。当消耗细胞能量、提高AMP/三磷酸腺苷(adenosine triphosphate,ATP)比值的生理和病理刺激时,如营养缺乏、剧烈活动、热休克、代谢性酸中毒、氧化应激和缺血、缺氧等,均能激     

Hypothalamic AMP-activated protein kinase mediates counter-regulatory responses to hypoglycaemia in rats

Aims/hypothesis Appropriate counter-regulatory hormonal responses are essential for recovery from hypoglycaemia. Although the hypothalamus is known to be involved in these responses, the molecular mechanisms have not been fully elucidated. AMP-activated protein kinase (AMPK) functions as a cellular energy sensor, being activated during energy depletion. As AMPK is expressed in the hypothalamus, an important site of neuroendocrine regulation, the present study was undertaken to determine whether hypothalamic AMPK mediates counter-regulatory responses to hypoglycaemia.Materials and methods Hypoglycaemia was induced by i.p. injection of regular insulin (6 U/kg) in Sprague–Dawley rats. Hypothalamic AMPK phosphorylation and activities were determined 1 h after i.p. insulin injection. To investigate the role of hypothalamic AMPK activation in mediating counter-regulatory responses, an AMPK inhibitor, compound C, was pre-administered intracerebroventricularly (i.c.v.) or dominantnegative (DN)-AMPK was overexpressed in the hypothalamus before induction of hypoglycaemia.Results Insulin-induced hypoglycaemia increased hypothalamic AMPK phosphorylation and 2-AMPK activities in rats. The change was significant in the arcuate nucleus/ventromedial hypothalamus (ARC/VMH) and paraventricular nuclei (PVN). Prior i.c.v. administration of compound C attenuated hypoglycaemia-induced increases in plasma concentrations of corticosterone, glucagon and catecholamines, resulting in severe and prolonged hypoglycaemia. ARC/VMH DN-AMPK overexpression impaired early counter-regulation, as evidenced by reduced glucagon and catecholamine responses. In contrast, PVN DN-AMPK overexpression attenuated late counter-regulation and corticosterone responses.Conclusions/interpretation Systemic hypoglycaemia causes hypothalamic AMPK activation, which is important for counter-regulatory hormonal responses. Our data indicate that hypothalamic AMPK acts as a fuel gauge, sensing the whole-body energy state and regulating not only energy homeostasis but also neuroendocrine functions.Electronic supplementary material Supplementary material is available for this article at .     

单磷酸腺苷活化蛋白激酶与肾脏疾病

单磷酸腺苷活化蛋白激酶(AMPK)是体内一种重要的蛋白激酶,广泛分布于全身各组织器官,发挥不同的功能.AMPK作为“细胞能量调节器”来调节糖、脂代谢及蛋白质合成,并参与调控机体炎症反应和细胞增生等过程,参与多种疾病(如动脉粥样硬化、肿瘤、糖尿病和其他代谢性疾病)的发生发展.近年来随着研究的深入,AMPK与肾脏疾病的关系逐渐受到关注.     

AMPK-能量代谢感受器与可激活AMPK相关的药物研究进展

单磷酸腺苷活化蛋白激酶（AMPK）可以感受细胞能量代谢变化,调节细胞的葡萄糖、脂肪酸的代谢过程。AMPK与细胞生长、生存和多种代谢信号途径关系密切,研究发现AMPK信号途径涉及炎症、肿瘤和代谢疾病。本文综述AMPK的功能与炎症、肿瘤、代谢类疾病的关系和诸如水杨酸、二甲双胍等药物激活AMPK的研究进展。     

脂联素通过LKB1途径激活腺苷酸活化蛋白激酶

目的 探讨脂联素是否通过LKB1途径激活骨骼肌及肝脏中腺苷酸活化蛋白激酶(AMPK).方法 将28只6周龄雄性Sprague-Dawley大鼠分为普通饮食组(NC组,n=15)和高脂饮食组(HF组,n=13).喂养16 周后,取空腹静脉血测定血清游离脂肪酸(FFA)、甘油三酯(TG)、总胆固醇(TC)、空腹血糖(FPG)、空腹胰岛素(FINS)及脂联素.采用Western印迹法测定各组大鼠骨骼肌及肝脏组织中AMPKα、磷酸化的AMPKcα和LKB1蛋白的表达.将原代培养的骨骼肌细胞及肝细胞分别予以脂联素和根赤壳菌素干预,免疫荧光技术测定各组细胞中AMPKα、磷酸化AMPKα和LKB1蛋白的表达.结果 与NC组比较,HF组大鼠体重、FFA、TG、FPG、FINS均升高(均P＜0.05),脂联素水平降低(P＜0.05).骨骼肌及肝组织巾AMPKα磷酸化和LKB1蛋白表达水平降低(均P＜0.05).原代培养大鼠骨骼肌细胞及肝细胞中脂联素显著增加AMPKα磷酸化及LKB1表达水平(均P＜0.05).加入根赤壳菌素表达明显降低(均P＜0.05).结论 脂联素在大鼠骨骼肌和肝脏组织可能通过LKB1途径激活AMPK.     

腺苷酸活化蛋白激酶在酒精性肝病中的研究进展

腺苷酸激活蛋白激酶（AMPK）信号通路是调节细胞能量状态的中心环节,其激活后磷酸化下游的信号分子,抑制ATP合成,同时促进ATP分解,被称为“细胞能量调节器”,在增加脂肪酸氧化、胰岛素敏感性及氧化应激等方面发挥重要作用,可能参与酒精性肝病的发病过程。该文就AMPK在酒精性肝病发病机制中的作用作一综述。     

Deficiency in AMP-activated protein kinase exaggerates high fat diet-induced cardiac hypertrophy and contractile dysfunction

AMPK, a metabolic sensor, protects against ischemic injury and cardiac hypertrophy although its role in obesity is unclear. This study was designed to examine the impact of AMPK deficiency on cardiac dysfunction following high fat feeding. Adult WT and transgenic mice overexpressing a kinase dead (KD) α2 isoform (K45R mutation) of AMPK were fed a low or high fat diet for 20 weeks. DEXA was used to confirm adiposity. Wheat germ agglutinin immunostaining was used to evaluate myocardial histology. Myocardial function was evaluated using echocardiography and edge-detection. AMPK activity was analyzed using fluorescence polarization assays. [1-¹⁴C] oleate was used to determine fatty acid oxidation. Expression of AMPK, α1, α2, ACC, Akt, the Glut-4 translocation mediator Akt substrate of 160KD (AS160), mTOR, total and membrane Glut-4 was evaluated using Western blot. AMPK activity was decreased in KD mice regardless of diet regimen. High fat diet led to obesity, glucose intolerance and cardiac hypertrophy with accentuated glucose intolerance, dampened fatty acid oxidation and cardiac hypertrophy in KD mice. High fat feeding triggered lower fractional shortening, increased LV mass, left ventricular end diastolic/systolic diameter, decreased PS, ± dL/dt, prolonged TR₉₀ and intracellular Ca²⁺ mishandling with a more pronounced effect in KD mice. High fat diet and AMPK KD lessened AMPKα2 isoform activity and ACC phosphorylation. AMPK deficiency unveiled or accentuated high fat diet-induced decrease in phosphorylation of Akt and AS160, membrane fraction of Glut-4 and mTOR expression (a greater mTOR phosphorylation). Taken together, these data suggest that AMPK deficiency exacerbates obesity-induced cardiac hypertrophy and contractile dysfunction, possibly associated with AS160 and mTOR signaling.     

AMP-活化蛋白激酶与缺血性脑血管病

作为细胞内的能量感受器，AMP-活化蛋白激酶(AMP-activated protein kinase,AMPK)在维持细胞和机体能量平衡中发挥着重要作用。最初，AMPK在糖尿病、肥胖等代谢性疾病的病理生理学过程中的作用研究较多；近年来，AMPK在脑组织中的分布以及酸中毒、氧化应激损伤和细胞凋亡等病理生理学过程中的作用日益受到重视。同时发现，卒中后人为调节AMPK活性可改变神经细胞结局。因此，AMPK有望成为治疗缺血性脑血管病的新靶点。     

T3-induced liver AMP-activated protein kinase signaling: Redox dependency and upregulation of downstream targets

AIM: To investigate the redox dependency and promotion of downstream targets in thyroid hormone (T₃)-induced AMP-activated protein kinase (AMPK) signaling as cellular energy sensor to limit metabolic stresses in the liver. METHODS: Fed male Sprague-Dawley rats were given a single ip dose of 0.1 mg T₃/kg or T₃ vehicle (NaOH 0.1 N; controls) and studied at 8 or 24 h after treatment. Separate groups of animals received 500 mg N-acetylcysteine (NAC)/kg or saline ip 30 min prior T₃. Measurements included plasma and liver 8-isoprostane and serum β-hydroxybutyrate levels (ELISA), hepatic levels of mRNAs (qPCR), proteins (Western blot), and phosphorylated AMPK (ELISA). RESULTS: T₃ upregulates AMPK signaling, including the upstream kinases Ca²⁺-calmodulin-dependent protein kinase kinase-β and transforming growth factor-β-activated kinase-1, with T₃-induced reactive oxygen species having a causal role due to its suppression by pretreatment with the antioxidant NAC. Accordingly, AMPK targets acetyl-CoA carboxylase and cyclic AMP response element binding protein are phosphorylated, with the concomitant carnitine palmitoyltransferase-1α (CPT-1α) activation and higher expression of peroxisome proliferator-activated receptor-γ co-activator-1α and that of the fatty acid oxidation (FAO)-related enzymes CPT-1α, acyl-CoA oxidase 1, and acyl-CoA thioesterase 2. Under these conditions, T₃ induced a significant increase in the serum levels of β-hydroxybutyrate, a surrogate marker for hepatic FAO. CONCLUSION: T₃ administration activates liver AMPK signaling in a redox-dependent manner, leading to FAO enhancement as evidenced by the consequent ketogenic response, which may constitute a key molecular mechanism regulating energy dynamics to support T₃ preconditioning against ischemia-reperfusion injury.     

腺苷酸活化的蛋白激酶通过SP1抑制下丘脑GT1-7神经元KiSS-1基因表达的机制研究

在GT1-7细胞用实时定量PCR检测腺苷酸活化的蛋白激酶(AMPK)对KiSS-1mRNA水平的影响,以报告基因技术检测KiSS-1基因启动子的活性,用Western印迹法检测AMPK对转录因子SP1蛋白表达及其在亚细胞中分布的影响.结果显示,AMPK能降低GT1-7细胞KiSS-1mRNA的表达水平,并能抑制KiSS-1基因的启动子活性;SP1能够增强KiSS-1基因的启动子活性;AMPK能够抑制SP1向细胞核的转位.提示AMPK可能通过抑制转录因子SP1的转位而降低KiSS-1基因的表达.