二甲双胍在大鼠酒精性肝损伤中的保护作用及其机制

酒精性肝病(ALD)的发病与脂质代谢紊乱、肝细胞线粒体内脂肪酸氧化障碍和氧化应激等有关[1-2].腺苷酸活化蛋白激酶(AMPK)被称为细胞的"代谢感受器",存在于线粒体内,其信号通路是调节细胞能量状态的中心环节,AMPK激活后可以提高胰岛素敏感性、增加脂肪酸氧化及改善氧化应激.二甲双胍是AMPK的变构激活剂,可以通过调节AMPK、胰岛素受体(INSR)和固醇调节元件结合蛋白(SREBP)的表达来改善胰岛素抵抗,减轻酒精所致的肝脏损伤.本研究旨在探讨二甲双胍通过改善胰岛素抵抗而预防酒精性肝病的作用机制.     

AMPK与肥胖

能量代谢平衡失调是肥胖发生的主要原因。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,关闭消耗ATP的合成代谢途径,开启产生ATP的分解代谢途径,被称为"细胞能量调节器",在增加骨骼肌对葡萄糖的摄取、增强胰岛素敏感性、增加脂肪酸氧化以及调节基因转录等方面发挥重要作用。在整体水平,AMPK通过激素和细胞因子如瘦素、脂联素和ghrelin等调节能量的摄入和消耗。研究AMPK与肥胖的关系,将为AMPK作为防治肥胖的新靶点提供可靠的理论基础和应用依据。     

AMPK对缺血心肌保护机制的研究进展

单磷酸腺苷活化的蛋白激酶(AMP-activated protein kinase，AMPK)广泛存在于心肌细胞中，其是细胞的能量感受器，参与细胞能量代谢调节，在生理和病理情况下都发挥着重要的功能。当细胞发生缺血、缺氧等应激反应时，细胞中三磷酸腺苷(ATP)的浓度降低，AMP的浓度升高，AMP/ATP的比例升高，AMPK被激活。激活的AMPK一方面可抑制ATP的消耗，另一方面刺激细胞产生更多的ATP，使细胞内ATP总量增多，从而可有限地延长细胞内ATP的供应时间，发挥对缺血心肌细胞的保护作用。此外，AMPK激活后可抑制蛋白质合成，可能通过减轻内质网应激以减少缺血引起的心肌细胞凋亡，发挥对心肌的保护作用。     

心血管疾病与非酒精性脂肪性肝病

心血管疾病(CVD)与非酒精性脂肪性肝病(NAFLD)在病理生理方面有着共同的机制,其中胆汁酸、能量和脂质代谢的相关信号分子在两种疾病的发生发展过程中均发挥了重要的作用。参与胆汁酸、能量和脂肪代谢的相关信号分子主要分别有法尼酯受体和胆汁酸G蛋白偶联胆汁酸受体1;成纤维生长因子21和AMPK激活的蛋白激酶;过氧化物酶体增殖物激活受体。可以针对其靶向分子进行药物干预,达到治疗的作用。     

AMPK与胰岛β细胞功能

腺苷酸活化蛋白激酶(AMPK)作为机体能量监测器,其活性主要受AMP/ATP比例调控。通过抑制能量合成,加速能量分解和ATP合成以保持机体能量平衡的同时,AMPK同样参与了胰岛β细胞胰岛素分泌的调节,并直接作用于β细胞的相关基因表达和胰岛素信号转导。以二甲双胍、罗格列酮、瘦素和脂联素为代表的AMPK激活剂对胰岛素分泌的直接影响尚有争议。本文就AMPK介导的胰岛β细胞功能作一简述。     

硝化应激在酒精性肝病中的作用

在酒精性肝病发病过程中存在诱导型一氧化氮合酶的表达增强,生成大量一氧化氮,在氧化应激的状态下与活性氧反应生成过氧化亚硝酸根离子,从而引发硝化应激,通过介导蛋白质、核酸等的硝化,影响细胞信号转导通路,最终影响细胞的代谢等功能及细胞凋亡,参与酒精性肝病的发病。本文旨在阐述硝化应激在酒精性肝病发病机制中可能发挥的作用。     

AMPK在肿瘤研究中的新进展

腺苷酸活化蛋白激酶(AMPK)是细胞内的能量感受器,在真核细胞生物中广泛存在.各种导致细胞内AMP/ATP比值升高的因素均可引起AMPK活化.AMPK活化后抑制消耗ATP的合成代谢过程,启动生成ATP的分解代谢过程,维持机体能量代谢平衡.AMPK家族成员与糖尿病等代谢性疾病关系密切.AMPK激活剂二甲双胍和噻唑烷二酮类,已作为2型糖尿病的治疗药物应用于临床.近来有研究表明肿瘤细胞中存在能量代谢异常,AMPK作为细胞能量代谢的调控因子,有望成为肿瘤治疗的新靶点.     

胆汁酸相关非酒精性脂肪性肝病发病机制及其药物治疗的研究进展

非酒精性脂肪性肝病发病率增加,已成为一个新的全球卫生问题。非酒精性脂肪性肝炎为其进展形式,预后不良,亟待寻找预防疾病进展并进行治疗的方法。胆汁酸作为一个重要的代谢物和信号分子,能够在肝内和肝外组织调节脂类和碳水化合物代谢以及能量平衡。胆汁酸与其受体如法尼酯X受体和Takeda G蛋白偶联受体5、胆汁酸转运蛋白、肠道菌群等相互作用,可以在不同层面参与非酒精性脂肪性肝病/非酒精性脂肪性肝炎的发病机理。总结了胆汁酸相关非酒精性脂肪性肝病发病机制及其药物治疗的研究进展。     

哺乳动物雷帕霉素靶蛋白C1(mTORC1)在非酒精性脂肪性肝病治疗中的作用机制及潜力

非酒精性脂肪性肝病(NAFLD)已成为全球最常见的慢性肝病，可进展为非酒精性脂肪性肝炎、肝硬化和肝癌。哺乳动物雷帕霉素靶蛋白(mTOR)是一种非典型丝氨酸/苏氨酸蛋白激酶，在细胞生长、凋亡、自噬及代谢等过程中发挥了极为重要的作用。本文阐述mTORC1信号通路在NAFLD发病过程中对细胞代谢和生长分化的作用，进一步提出mTORC1通路对于NAFLD治疗药物的研究价值和潜力。     

细胞凋亡与肥胖相关的非酒精性脂肪性肝病

近年来，肥胖相关的非酒精性脂肪性肝病的发病率呈上升趋势，并严重影响着人们的健康。其中细胞凋亡及其相关因素肿瘤坏死因子-α，Fas系统，核因子-κB及组织蛋白酶B在肥胖相关的非酒精性脂肪性肝病的发病机制中起了重要的作用。本文概括综述细胞凋亡与其相关因素在肥胖相关的非酒精性脂肪性肝病中的作用。     

解偶联蛋白2与酒精性肝病

解偶联蛋白2(UCP2)是线粒体内膜上可以调节质子跨膜转运的载体蛋白,可以驱散质子电化学梯度,使氧化呼吸与ATP合成解偶联。UCP2与能量消耗和脂质代谢密切相关,可能参与酒精性肝病(ALD)发病过程中的氧化应激和脂质过氧化。进一步探讨UCP2在ALD中的作用对于ALD的防治具有重要意义。     

AMPK - Activated Protein Kinase and its Role in Energy Metabolism of the Heart

Adenosine monophosphate - activated kinase (AMPK) plays a key role in the coordination of the heart's anabolic and catabolic pathways. It induces a cellular cascade at the center of maintaining energy homeostasis in the cardiomyocytes.. The activated AMPK is a heterotrimeric protein, separated into a catalytic α - subunit (63kDa), a regulating β - subunit (38kDa) and a γ - subunit (38kDa), which is allosterically adjusted by adenosine triphosphate (ATP) and adenosine monophosphate (AMP). The actual binding of AMP to the γ - subunit is the step which activates AMPK. AMPK serves also as a protein kinase in several metabolic pathways of the heart, including cellular energy sensoring or cardiovascular protection. The AMPK cascade represents a sensitive system, activated by cellular stresses that deplete ATP and acts as an indicator of intracellular ATP/AMP. In the context of cellular stressors (i.e. hypoxia, pressure overload, hypertrophy or ATP deficiency) the increasing levels of AMP promote allosteric activation and phosphorylation of AMPK. As the concentration of AMP begins to increase, ATP competitively inhibits further phosphorylation of AMPK. The increase of AMP may also be induced either from an iatrogenic emboli, percutaneous coronary intervention, or from atherosclerotic plaque rupture leading to an ischemia in the microcirculation. To modulate energy metabolism by phosphorylation and dephosphorylation is vital in terms of ATP usage, maintaining transmembrane transporters and preserving membrane potential. In this article, we review AMPK and its role as an important regulatory enzyme during periods of myocardial stress, regulating energy metabolism, protein synthesis and cardiovascular protection.     

N488I mutation of the gamma2-subunit results in bidirectional changes in AMP-activated protein kinase activity

Mutations in the human gene encoding the nucleotide-binding region in the gamma-subunit of AMP-activated protein kinase (AMPK) cause cardiomyopathy with preexcitation syndrome. Mutant AMPK showed reduced binding affinity to nucleotides in vitro raising the possibility that altered regulation of AMPK activity by AMP/ATP could contribute to the disease phenotype. In this study, we determined the sensitivity of AMPK activity to AMP/ATP in the beating hearts using transgenic mice expressing a mutant (N488I, gamma2-mutant) or wild-type gamma2-subunit (gamma2-TG). The [ATP] and [AMP] were unaltered in all hearts but the AMPK activity was increased by 2.5-fold in gamma2-mutant hearts freeze-clamped at normal AMP/ATP compared with nontransgenic (WT) or gamma2-TG. The increased basal AMPK activity was caused by increased Thr-172 phosphorylation of the alpha-subunit (p-AMPK, by 4-fold) at normal [ATP] and was not changed by reducing glycogen content by 60% in the gamma2-mutant hearts. A reversal of AMP/ATP, caused by ATP degradation, increased p-AMPK by 7-fold in WT but caused no change in gamma2-mutant hearts. These results demonstrate that the mutation renders AMPK insensitive to the inhibitory and stimulatory effects of the regulatory nucleotides ATP and AMP, respectively, suggesting that the pathogenesis of the human disease may not be attributable to a simple loss- or gain-of-function.     

Antioxidant and anti-inflammatory agents in chronic liver diseases: Molecular mechanisms and therapy

Chronic liver disease (CLD) is a continuous process that causes a reduction of liver function lasting more than six months. CLD includes alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), chronic viral infection, and autoimmune hepatitis, which can lead to liver fibrosis, cirrhosis, and cancer. Liver inflammation and oxidative stress are commonly associated with the development and progression of CLD. Molecular signaling pathways such as AMP-activated protein kinase (AMPK), C-Jun N-terminal kinase, and peroxisome proliferator-activated receptors (PPARs) are implicated in the pathogenesis of CLD. Therefore, antioxidant and anti-inflammatory agents from natural products are new potent therapies for ALD, NAFLD, and hepatocellular carcinoma (HCC). In this review, we summarize some powerful products that can be potential applied in all the stages of CLD, from ALD/NAFLD to HCC. The selected agents such as β-sitosterol, curcumin, genistein, and silymarin can regulate the activation of several important molecules, including AMPK, Farnesoid X receptor, nuclear factor erythroid 2-related factor-2, PPARs, phosphatidylinositol-3-kinase, and lysyl oxidase-like proteins. In addition, clinical trials are undergoing to evaluate their efficacy and safety.     

AMP-activated protein kinase in metabolic control and insulin signaling

The AMP-activated protein kinase (AMPK) system acts as a sensor of cellular energy status that is conserved in all eukaryotic cells. It is activated by increases in the cellular AMP:ATP ratio caused by metabolic stresses that either interfere with ATP production (eg, deprivation for glucose or oxygen) or that accelerate ATP consumption (eg, muscle contraction). Activation in response to increases in AMP involves phosphorylation by an upstream kinase, the tumor suppressor LKB1. In certain cells (eg, neurones, endothelial cells, and lymphocytes), AMPK can also be activated by a Ca(2+)-dependent and AMP-independent process involving phosphorylation by an alternate upstream kinase, CaMKKbeta. Once activated, AMPK switches on catabolic pathways that generate ATP, while switching off ATP-consuming processes such as biosynthesis and cell growth and proliferation. The AMPK complex contains 3 subunits, with the alpha subunit being catalytic, the beta subunit containing a glycogen-sensing domain, and the gamma subunits containing 2 regulatory sites that bind the activating and inhibitory nucleotides AMP and ATP. Although it may have evolved to respond to metabolic stress at the cellular level, hormones and cytokines such as insulin, leptin, and adiponectin can interact with the system, and it now appears to play a key role in maintaining energy balance at the whole body level. The AMPK system may be partly responsible for the health benefits of exercise and is the target for the antidiabetic drug metformin. It is a key player in the development of new treatments for obesity, type 2 diabetes, and the metabolic syndrome.     

Functional characterization of the adrenoleukodystrophy protein (ALDP) and disease pathogenesis

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder characterized by abnormal accumulation of saturated very long chain fatty acids in tissues and body fluids with predominance in brain white matter and adrenal cortex. The clinical phenotype is highly variable ranging from the severe childhood cerebral form to asymptomatic persons. The responsible ALD gene encodes the adrenoleukodystrophy protein (ALDP), a peroxisomal integral membrane protein that is a member of the ATP-binding cassette (ABC) transporter protein family. The patient gene mutations are heterogeneously distributed over the functional domains of ALDP. The extreme variability in clinical phenotype, even within one affected family, indicates that besides the ALD gene mutations other factors strongly influence the clinical phenotype. To understand the cell biology and function of mammalian peroxisomal ABC transporters and to determine their role in the pathogenesis of X-ALD we developed a system for expressing functional ABC protein domains in fusion with the maltose binding protein. Wild type and mutant fusion proteins of the nucleotide-binding fold were overexpressed, purified, and characterized by photoaffinity labeling with 8-azido ATP or 8-azido GTP and a coupled ATP regenerating enzyme assay for ATPase activity. Our studies provide evidence that peroxisomal ABC transporters utilize ATP to become a functional transporter and that ALD gene mutations alter peroxisomal transport function. The established disease model will be used further to study the influence of possible disease modifier proteins on ALDP function.     

The regulation of AMP-activated protein kinase by upstream kinases

AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that plays a major role in maintaining energy homoeostasis. Within individual cells, AMPK is activated by a rise in the AMP/ATP ratio that occurs following a fall in ATP levels. AMPK is also regulated by the adipokines, adiponectin and leptin, hormones that are secreted from adipocytes. AMPK regulates a wide range of metabolic pathways, including fatty acid oxidation, fatty acid synthesis, glycolysis and gluconeogenesis. In peripheral tissues, activation of AMPK leads to responses that are beneficial in counteracting the deleterious effects that arise in the metabolic syndrome. Recent studies have demonstrated that modulation of AMPK activity in the hypothalamus plays a role in feeding. A decrease in hypothalamic AMPK activity is associated with decreased feeding, whereas activation of AMPK leads to increased food intake. Furthermore, signalling pathways occurring in the hypothalamus lead to changes in AMPK activity in peripheral tissues, such as skeletal muscle, via the sympathetic nervous system. AMPK, therefore, provides a mechanism for monitoring changes in energy metabolism within individual cells and at the level of the whole body. Activation of AMPK requires phosphorylation of threonine 172 (Thr-172) within the catalytic subunit. Recent studies have shown that both LKB1 and Ca(2+)/calmodulin-dependent protein kinase kinase-beta (CaMKKbeta) play important roles in phosphorylating and activating AMPK. In addition, there is evidence that AMPK can be activated by other upstream kinases, although the physiological significance of this is not clear at present. This review focuses on the role of LKB1 and CaMKKbeta in the regulation of AMPK.     

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。     

AMP-activated protein kinase connects cellular energy metabolism to KATP channel function

AMPK is an important sensor of cellular energy levels. The aim of these studies was to investigate whether cardiac K(ATP) channels, which couple cellular energy metabolism to membrane excitability, are regulated by AMPK activity. We investigated effects of AMPK on rat ventricular K(ATP) channels using electrophysiological and biochemical approaches. Whole-cell K(ATP) channel current was activated by metabolic inhibition; this occurred more rapidly in the presence of AICAR (an AMPK activator). AICAR had no effects on K(ATP) channel activity recorded in the inside-out patch clamp configuration, but ZMP (the intracellular intermediate of AICAR) strongly activated K(ATP) channels. An AMPK-mediated effect is demonstrated by the finding that ZMP had no effect on K(ATP) channels in the presence of Compound C (an AMPK inhibitor). Recombinant AMPK activated Kir6.2/SUR2A channels in a manner that was dependent on the AMP concentration, whereas heat-inactivated AMPK was without effect. Using mass-spectrometry and co-immunoprecipitation approaches, we demonstrate that the AMPK α-subunit physically associates with K(ATP) channel subunits. Our data demonstrate that the cardiac K(ATP) channel function is directly regulated by AMPK activation. During metabolic stress, a small change in cellular AMP that activates AMPK can be a potential trigger for K(ATP) channel opening. This article is part of a Special Issue entitled "Local Signaling in Myocytes".