Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.31 (AMP-activated protein kinase)
 13,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

AMP-activated protein kinase (AMPK) is a metabolic fuel gauge conserved along the evolutionary scale in eukaryotes that senses changes in the intracellular AMP/ATP ratio. Recent evidence indicated an important role for AMPK in the therapeutic benefits of metformin, thiazolidinediones and exercise, which form the cornerstones of the clinical management of type 2 diabetes and associated metabolic disorders. In general, activation of AMPK acts to maintain cellular energy stores, switching on catabolic pathways that produce ATP, mostly by enhancing oxidative metabolism and mitochondrial biogenesis, while switching off anabolic pathways that consume ATP. This regulation can take place acutely, through the regulation of fast post-translational events, but also by transcriptionally reprogramming the cell to meet energetic needs. Here we demonstrate that AMPK controls the expression of genes involved in energy metabolism in mouse skeletal muscle by acting in coordination with another metabolic sensor, the NAD+-dependent type III deacetylase SIRT1. AMPK enhances SIRT1 activity by increasing cellular NAD+ levels, resulting in the deacetylation and modulation of the activity of downstream SIRT1 targets that include the peroxisome proliferator-activated receptor-gamma coactivator 1alpha and the forkhead box O1 (FOXO1) and O3 (FOXO3a) transcription factors. The AMPK-induced SIRT1-mediated deacetylation of these targets explains many of the convergent biological effects of AMPK and SIRT1 on energy metabolism.
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PMID:AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. 1926 8

Mitochondria are dynamic organelles that integrate environmental signals to regulate energy production, apoptosis and Ca(2+) homeostasis. Not surprisingly, mitochondrial dysfunction is associated with aging and the pathologies observed in age-related diseases. The vast majority of mitochondrial proteins are encoded in the nuclear genome, and so communication between the nucleus and mitochondria is essential for maintenance of appropriate mitochondrial function. Several proteins have emerged as major regulators of mitochondrial gene expression, capable of increasing transcription of mitochondrial genes in response to the physiological demands of the cell. In this review, we will focus on PGC-1alpha, SIRT1, AMPK and mTOR and discuss how these proteins regulate mitochondrial function and their potential involvement in aging, calorie restriction and age-related disease. We will also discuss the pathways through which mitochondria signal to the nucleus. Although such retrograde signaling is not well studied in mammals, there is growing evidence to suggest that it may be an important area for future aging research. Greater understanding of the mechanisms by which mitochondria and the nucleus communicate will facilitate efforts to slow or reverse the mitochondrial dysfunction that occurs during aging.
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PMID:The coordination of nuclear and mitochondrial communication during aging and calorie restriction. 1949 Oct 41

Alcoholic fatty liver is a major risk factor for advanced liver injuries such as steatohepatitis, fibrosis, and cirrhosis. While the underlying mechanisms are multiple, the development of alcoholic fatty liver has been attributed to a combined increase in the rate of de novo lipogenesis and a decrease in the rate of fatty acid oxidation in animal liver. Among various transcriptional regulators, the hepatic SIRT1 (sirtuin 1)-AMPK (AMPK-activated kinase) signaling system represents a central target for the action of ethanol in the liver. Adiponectin is one of the adipocyte-derived adipokines with potent lipid-lowering properties. Growing evidence has demonstrated that the development of alcoholic fatty liver is associated with reduced circulating adiponectin levels, decreased hepatic adiponectin receptor expression, and impaired hepatic adiponectin signaling. Adiponectin confers protection against alcoholic fatty liver via modulation of complex hepatic signaling pathways largely controlled by the central regulatory system, SIRT1-AMPK axis. This review aims to integrate the current research findings of ethanol-mediated dysregulation of adiponectin and its receptors and to provide a comprehensive point of view for understanding the role of adiponectin signaling in the development of alcoholic fatty liver.
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PMID:Adiponectin: a key adipokine in alcoholic fatty liver. 1949 77

Arachidonic acid (AA, a proinflammatory fatty acid) in combination with iron promotes excess reactive oxygen species (ROS) production and exerts a deleterious effect on mitochondria. We have shown previously that activation of AMP-activated protein kinase (AMPK) protects hepatocytes from AA + iron-induced apoptosis. Resveratrol, a polyphenol in grapes, has beneficial effects mediated through SIRT1, LKB1, and AMPK. This study investigated the potential of resveratrol to protect against the mitochondrial impairment induced by AA + iron and the underlying mechanism for this cytoprotection. Resveratrol treatment inhibited apoptosis, ROS production, and glutathione depletion elicited by AA + iron in HepG2 cells. In addition, resveratrol attenuated superoxide generation in mitochondria and inhibited mitochondrial dysfunction induced by AA + iron. Overall, AMPK activation by resveratrol contributed to cell survival, as supported by the reversal of its restoration of mitochondrial membrane potential by either overexpression of a dominant-negative mutant of AMPKalpha or compound C treatment. Resveratrol increased inhibitory phosphorylation of glycogen synthase kinase-3beta (GSK3beta) downstream of AMPK, which contributed to mitochondrial protection and cell survival. Likewise, small interfering RNA knockdown of LKB1, an upstream kinase of AMPK, reduced the ability of resveratrol to protect cells from mitochondrial dysfunction. Furthermore, this LKB1-dependent mitochondrial protection resulted from resveratrol's poly(ADP-ribose)polymerase activation, but not SIRT1 activation, as supported by the experiment using 3-aminobenzamide, a poly(ADP-ribose)polymerase inhibitor. Other polyphenols, such as apigenin, genistein, and daidzein, did not activate AMPK or protect mitochondria against AA + iron. Thus, resveratrol protects cells from AA + iron-induced ROS production and mitochondrial dysfunction through AMPK-mediated inhibitory phosphorylation of GSK3beta downstream of poly(ADP-ribose)polymerase-LKB1 pathway.
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PMID:Resveratrol protects mitochondria against oxidative stress through AMP-activated protein kinase-mediated glycogen synthase kinase-3beta inhibition downstream of poly(ADP-ribose)polymerase-LKB1 pathway. 3061 99

High glucose-induced protein synthesis in the glomerular epithelial cell (GEC) is partly dependent on reduction in phosphorylation of AMP-activated protein kinase (AMPK). We evaluated the effect of resveratrol, a phytophenol known to stimulate AMPK, on protein synthesis. Resveratrol completely inhibited high glucose stimulation of protein synthesis and synthesis of fibronectin, an important matrix protein, at 3 days. Resveratrol dose-dependently increased AMPK phosphorylation and abolished high glucose-induced reduction in its phosphorylation. We examined the effect of resveratrol on critical steps in mRNA translation, a critical event in protein synthesis. Resveratrol inhibited high glucose-induced changes in association of eIF4E with eIF4G, phosphorylation of eIF4E, eEF2, eEF2 kinase and, p70S6 kinase, indicating that it affects important events in both initiation and elongation phases of mRNA translation. Upstream regulators of AMPK in high glucose-treated GEC were explored. High glucose augmented acetylation of LKB1, the upstream kinase for AMPK, and inhibited its activity. Resveratrol prevented acetylation of LKB1 and restored its activity in high glucose-treated cells; this action did not appear to depend on SIRT1, a class III histone deacetylase. Our data show that resveratrol ameliorates protein synthesis by regulating the LKB1-AMPK axis.
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PMID:Resveratrol ameliorates high glucose-induced protein synthesis in glomerular epithelial cells. 1976 49

SIRT1 is the closest mammalian homologue of enzymes that extend life in lower organisms. Its role in mammals is incompletely understood, but includes modulation of at least 34 distinct targets through its nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase activity. Recent experiments using small molecule activators and genetically engineered mice have provided new insight into the role of this enzyme in mammalian biology and helped to highlight some of the potentially relevant targets. The most widely employed activator is resveratrol, a small polyphenol that improves insulin sensitivity and vascular function, boosts endurance, inhibits tumor formation, and ameliorates the early mortality associated with obesity in mice. Many of these effects are consistent with modulation of SIRT1 targets, such as PGC1alpha and NFkappaB, however, resveratrol can also activate AMPK, inhibit cyclooxygenases, and influence a variety of other enzymes. A novel activator, SRT1720, as well as various methods to manipulate NAD(+) metabolism, are emerging as alternative methods to increase SIRT1 activity, and in many cases recapitulate effects of resveratrol. At present, further studies are needed to more directly test the role of SIRT1 in mediating beneficial effects of resveratrol, to evaluate other strategies for SIRT1 activation, and to confirm the specific targets of SIRT1 that are relevant in vivo. These efforts are especially important in light of the fact that SIRT1 activators are entering clinical trials in humans, and "nutraceutical" formulations containing resveratrol are already widely available.
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PMID:Biochemical effects of SIRT1 activators. 1989 59

Since the discovery of NAD-dependent deacetylases, sirtuins, it has been recognized that maintaining intracellular levels of NAD is crucial for the management of stress response of cells. Here we show that agonist-induced cardiac hypertrophy is associated with loss of intracellular levels of NAD, but not exercise-induced physiologic hypertrophy. Exogenous addition of NAD was capable of maintaining intracellular levels of NAD and blocking the agonist-induced cardiac hypertrophic response in vitro as well as in vivo. NAD treatment blocked the activation of pro-hypertrophic Akt1 signaling, and augmented the activity of anti-hypertrophic LKB1-AMPK signaling in the heart, which prevented subsequent induction of mTOR-mediated protein synthesis. By using gene knock-out and transgenic mouse models of SIRT3 and SIRT1, we showed that the anti-hypertrophic effects of exogenous NAD are mediated through activation of SIRT3, but not SIRT1. SIRT3 deacetylates and activates LKB1, thus augmenting the activity of the LKB1-AMPK pathway. These results reveal a novel role of NAD as an inhibitor of cardiac hypertrophic signaling, and suggest that prevention of NAD depletion may be critical in the treatment of cardiac hypertrophy and heart failure.
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PMID:Exogenous NAD blocks cardiac hypertrophic response via activation of the SIRT3-LKB1-AMP-activated kinase pathway. 1994 Jan 31

Resveratrol, a polyphenol found in several vegetal sources, has been shown to possess lifespan-promoting properties in yeast and metazoans, including small mammals. While in yeast and low metazoans resveratrol acts mainly by activating the histone deacetylase Sir2, in mammals it appears to target - besides the Sir2 homolog SIRT1 - several crucial pathways for the control of metabolism, including the AMPK and the insulin-IGF1 receptors axis. The action of resveratrol on these pathways has been linked to its capability to i) prolong lifespan following chronic administration to mice and ii) protect from the development of diet-induced obesity and obesity-dependent metabolic disorders. Here we summarise the current understanding on how resveratrol displays its remarkable properties by acting on the control of insulin secretion and by modulation of insulin action in pheripheral insulin-responsive tissues. Since resveratrol has the potential for pharmacological exploitation to prevent the establishment of insulin-resistance and thus postpone - or even prevent - the onset of type 2 diabetes, toxicologic and pharmacodynamics studies in humans have been initiated. These studies show that resveratrol is non-toxic and easily absorbed by humans. As a drawback, its bioavailability is very limited due to the fast metabolic alterations to which it is subjected in the plasma. Therefore, we also review here the efforts that have been made - in the drug discovery field - to identify new molecules endowed with resveratrol-like pharmacological properties but with better bioavailability, which could prove to possess therapeutic potential.
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PMID:Metabolic effects of resveratrol in mammals--a link between improved insulin action and aging. 2002 85

Isoliquiritigenin (ILQ), a flavonoid compound originated from Glycyrrhiza species, is known to activate SIRT1. Arachidonic acid (AA) in combination with iron (a catalyst of auto-oxidation) leads cells to produce excess reactive species with a change in mitochondrial permeability transition. In view of the importance of oxidative stress in cell death and inflammation, this study investigated the potential of ILQ to protect cells against the mitochondrial impairment induced by AA+iron and the underlying basis for this cytoprotection. Treatment with ILQ inhibited apoptosis induced by AA+iron, as evidenced by alterations in the levels of the proteins associated with cell viability: ILQ prevented a decrease in Bcl-x(L), and cleavage of poly(ADP-ribose)polymerase and procaspase-3. Moreover, ILQ inhibited the ability of AA+iron to elicit mitochondrial dysfunction. In addition, superoxide generation in mitochondria was attenuated by ILQ treatment. Consistently, ILQ prevented cellular H2O2 production increased by AA+iron, thereby enabling cells to restore GSH content. ILQ treatment enhanced inhibitory phosphorylation of glycogen synthase kinase-3beta (GSK3beta), and prevented a decrease in the GSK3beta phosphorylation elicited by AA+iron, which contributed to protecting cells and mitochondria. GSK3beta phosphorylation by ILQ was preceded by AMP-activated protein kinase (AMPK) activation, which was also responsible for mitochondrial protection, as shown by reversal of its effect in the experiments using a dominant negative mutant of AMPK and compound C. Moreover, the AMPK activation led to GSK3beta phosphorylation. These results demonstrate that ILQ has the ability to protect cells from AA+iron-induced H2O2 production and mitochondrial dysfunction, which is mediated with GSK3beta phosphorylation downstream of AMPK.
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PMID:AMPK-mediated GSK3beta inhibition by isoliquiritigenin contributes to protecting mitochondria against iron-catalyzed oxidative stress. 2002 81

Abnormal elevation of hepatic gluconeogenesis is central to the onset of hyperglycaemia in patients with type 2 diabetes mellitus (T2DM). Metformin corrects hyperglycaemia through inhibition of gluconeogenesis, but its mechanism of action is yet to be fully described. SIRT1 and GCN5 (listed as KAT2A in the MGI Database) have recently been identified as regulators of gluconeogenic gene expression through modulation of levels and activity of the coactivators cAMP-response element binding protein-regulated transcription coactivator 2 (TORC2 or CRTC2 as listed in the MGI Database) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1alpha or PPARGC1A as listed in the MGI Database). We report that in db/db mice, metformin (250 mg/kg per day; 7 days) increases hepatic levels of GCN5 protein and mRNA compared with the untreated db/db mice, as well as increases levels of SIRT1 protein and activity relative to controls and untreated db/db mice. These changes were associated with reduced TORC2 protein level and decreased gene expression and activation of the PGC1alpha gene target phosphoenolpyruvate carboxykinase, and lower plasma glucose and insulin. Inhibition of SIRT1 partially blocked the effects of metformin on gluconeogenesis. SIRT1 was increased through an AMP-activated protein kinase-mediated increase in gene expression of nicotinamide phosphoribosyltransferase, the rate-limiting enzyme of the salvage pathway for NAD(+). Moreover, levels of GCN5 were dramatically reduced in db/db mice compared with the controls. This indicates that loss of GCN5-mediated inhibition of gluconeogenesis appears to constitute a major mechanism for the onset of abnormally elevated hepatic glucose production in db/db mice. In conclusion, induction of GCN5 and SIRT1 potentially represents a critical mechanism of action of metformin. In addition, these data identify induction of hepatic GCN5 as a potential therapeutic strategy for treatment of T2DM.
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PMID:Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5. 2009 81


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