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)

SIRT1, the mammalian homolog of SIR2 in Saccharomyces cerevisiae, is an NAD-dependent deacetylase implicated in regulation of lifespan. By designing effective short hairpin RNAs and a silent shRNA-resistant mutant SIRT1 in a genetically defined system, we show that efficient inhibition of SIRT1 in telomerase-immortalized human cells enhanced cell growth under normal and nutrient limiting conditions. Hematopoietic stem cells obtained from SIRT1-deficient mice also showed increased growth capacity and decreased dependency on growth factors. Consistent with this, SIRT1 inhibition was associated with increased telomerase activity in human cells. We also observed a significant increase in AMPK levels up on SIRT1 inhibition under glucose limiting conditions. Although SIRT1 suppression cooperated with hTERT to promote cell growth, either overexpression or suppression of SIRT1 alone had no effect on life span of human diploid fibroblasts. Our findings challenge certain models and connect nutrient sensing enzymes to the immortalization process. Furthermore, they show that in certain cell lineages, SIRT1 can act as a growth suppressor gene.
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PMID:SIRT1 acts as a nutrient-sensitive growth suppressor and its loss is associated with increased AMPK and telomerase activity. 1818 47

It is intuitive to speculate that nutrient availability may influence differentiation of mammalian cells. Nonetheless, a comprehensive complement of the molecular determinants involved in this process has not been elucidated yet. Here, we have investigated how nutrients (glucose) affect skeletal myogenesis. Glucose restriction (GR) impaired differentiation of skeletal myoblasts and was associated with activation of the AMP-activated protein kinase (AMPK). Activated AMPK was required to promote GR-induced transcription of the NAD+ biosynthetic enzyme Nampt. Indeed, GR augmented the Nampt activity, which consequently modified the intracellular [NAD+]:[NADH] ratio and nicotinamide levels, and mediated inhibition of skeletal myogenesis. Skeletal myoblasts derived from SIRT1+/- heterozygous mice were resistant to the effects of either GR or AMPK activation. These experiments reveal that AMPK, Nampt, and SIRT1 are the molecular components of a functional signaling pathway that allows skeletal muscle cells to sense and react to nutrient availability.
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PMID:Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt. 1847 47

The metabolic syndrome (MetS) encompasses a constellation of cardio-metabolic abnormalities associated with a high risk of developing type 2 diabetes and cardiovascular disease (CVD), the top killer in the ageing population. Recent studies have demonstrated multiple beneficial effects of moderate wine consumption in the protection against development of the MetS and its related medical complications. The association of moderate wine consumption with lower incidence of the MetS and atherosclerotic heart disease has been repeatedly documented in numerous epidemiological studies on diverse ethnic groups. In addition to the favorable effects of moderate ethanol intake on lipid profiles, polyphenols enriched in red wine possess multiple benefits on the MetS beyond alcohol through their anti-oxidant, anti-inflammatory, vascular-protective and insulin-sensitizing properties. Notable among these red wine polypheolic compounds is resveratrol, a phytoalexin that has recently attracted great attention due to its role in mimicking calorie restriction. This compound can act as a potent activator of the NAD(+)-dependent deacetylases sirtuins to expand the life span and to prevent the deleterious effects of excess intake on insulin resistance and metabolic derangement. In addition, resveratrol exerts its multiple protective effects against the MetS through stimulating AMP-activated protein kinase and promoting mitochondria biogenesis. In this review, we highlight the recent epidemiological and experimental evidences supporting the protective effects of moderate wine intake against the MetS and its associated cardio-metabolic complications, and discuss the molecular mechanisms underlying the multiple beneficial actions of red wine polyphenols with the focus on resveratrol.
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PMID:Moderate wine consumption in the prevention of metabolic syndrome and its related medical complications. 1853 95

The ability to adapt and respond to nutrients is an ancient cellular function, conserved from unicellular to the most complex multicellular organisms, including mammals. Mammals adapt to changes in nutritional status through the modulation of tissue-specific metabolic pathways so as to maintain energy homeostasis. At least two proteins are activated in response to reduced nutrient availability: AMP-activated protein kinase (AMPK) and NAD(+)-dependent deacetylase SIRT1. AMPK functions as a sensor of cellular energy status and as a master regulator of metabolism. When ATP levels decrease, AMPK is activated to boost ATP production and to inhibit ATP usage, thus restoring energy balance. Similarly, SIRT1 is activated in response to changes in the energy status to promote transcription of genes that mediate the metabolic response to stress, starvation or calorie restriction. Several observations support a model where, in response to stress and reduced nutrients, a metabolic pathway is activated within which AMPK and SIRT1 concordantly function to ensure an appropriate cellular response and adaptation to environmental modifications. In this perspective, we compare and contrast the roles of SIRT1 and AMPK in several metabolic tissues and propose a working model of how the AMPK-SIRT1 axis may be regulated to control functions relevant to organismal physiology and pathophysiology.
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PMID:Comparing and contrasting the roles of AMPK and SIRT1 in metabolic tissues. 1902 11

Alcoholic fatty liver is a potentially pathologic condition which can progress to steatohepatitis, fibrosis, and cirrhosis if alcohol consumption is continued. Alcohol exposure may induce fatty liver by increasing NADH/NAD(+) ratio, increasing sterol regulatory element-binding protein-1 (SREBP-1) activity, decreasing peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activity, and increasing complement C3 hepatic levels. Alcohol may increase SREBP-1 activity by decreasing the activities of AMP-activated protein kinase and sirtuin-1. Tumor necrosis factor-alpha (TNF-alpha) produced in response to alcohol exposure may cause fatty liver by up-regulating SREBP-1 activity, whereas betaine and pioglitazone may attenuate fatty liver by down-regulating SREBP-1 activity. PPAR-alpha agonists have potentials to attenuate alcoholic fatty liver. Adiponectin and interleukin-6 may attenuate alcoholic fatty liver by up-regulating PPAR-alpha and insulin signaling pathways while down-regulating SREBP-1 activity and suppressing TNF-alpha production. Recent studies show that paracrine activation of hepatic cannabinoid receptor 1 by hepatic stellate cell-derived endocannabinoids also contributes to the development of alcoholic fatty liver. Furthermore, oxidative modifications and inactivation of the enzymes involved in the mitochondrial and/or peroxisomal beta-oxidation of fatty acids could contribute to fat accumulation in the liver.
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PMID:Molecular mechanisms of alcoholic fatty liver. 1903 84

The NAD(+)-dependent deacetylase SIRT1 controls metabolic processes in response to low nutrient availability. We report the metabolic phenotype of mice treated with SRT1720, a specific and potent synthetic activator of SIRT1 that is devoid of direct action on AMPK. SRT1720 administration robustly enhances endurance running performance and strongly protects from diet-induced obesity and insulin resistance by enhancing oxidative metabolism in skeletal muscle, liver, and brown adipose tissue. These metabolic effects of SRT1720 are mediated by the induction of a genetic network controlling fatty acid oxidation through a multifaceted mechanism that involves the direct deacetylation of PGC-1alpha, FOXO1, and p53 and the indirect stimulation of AMPK signaling through a global metabolic adaptation mimicking low energy levels. Combined with our previous work on resveratrol, the current study further validates SIRT1 as a target for the treatment of metabolic disorders and characterizes the mechanisms underlying the therapeutic potential of SIRT1 activation.
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PMID:Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. 1904 67

BLX-1002 is a novel small thiazolidinedione with no apparent affinity to peroxisome proliferator-activated receptors (PPAR) that has been shown to reduce glycemia in type 2 diabetes without adipogenic effects. Its precise mechanisms of action, however, remain elusive, and no studies have been done with respect to possible effects of BLX-1002 on pancreatic beta-cells. We have investigated the influence of the drug on beta-cell function in mouse islets in vitro. BLX-1002 enhanced insulin secretion stimulated by high, but not low or intermediate, glucose concentrations. BLX-1002 also augmented cytoplasmic free Ca2+ concentration ([Ca2+](i)) at high glucose, an effect that was abolished by pretreatment with the Ca2+-ATPase inhibitor thapsigargin. In contrast, BLX-1002 did not interfere with voltage-gated Ca2+ channel or ATP-sensitive K+ channel activities. In addition, cellular NAD(P)H stimulated by glucose was not affected by the drug. The stimulatory effect of BLX-1002 on insulin secretion at high glucose was completely abolished by treatment with the phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin or LY-294002. Stimulation of the beta-cells with BLX-1002 also induced activation of AMP-activated protein kinase (AMPK) at high glucose. Our study suggests that BLX-1002 potentiates insulin secretion only at high glucose in beta-cells in a PI3K-dependent manner. This effect of BLX-1002 is associated with an increased [Ca2+](i) mediated through Ca2+ mobilization, and an enhanced activation of AMPK. The glucose-sensitive stimulatory impact of BLX-1002 on beta-cell function may translate into substantial clinical benefits of the drug in the management of type 2 diabetes, by avoidance of hypoglycemia.
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PMID:BLX-1002, a novel thiazolidinedione with no PPAR affinity, stimulates AMP-activated protein kinase activity, raises cytosolic Ca2+, and enhances glucose-stimulated insulin secretion in a PI3K-dependent manner. 1905 59

We examined in HepG2 cells whether glucose-induced changes in AMP-activated protein kinase (AMPK) activity could be mediated by SIRT1, an NAD(+)-dependent histone/protein deacetylase that has been linked to the increase in longevity caused by caloric restriction. Incubation with 25 vs. 5mM glucose for 6h concurrently diminished the phosphorylation of AMPK (Thr 172) and ACC (Ser 79), increased lactate release, and decreased the abundance and activity of SIRT1. In contrast, incubation with pyruvate (0.1 and 1mM) for 2h increased AMPK phosphorylation and SIRT1 abundance and activity. The putative SIRT1 activators resveratrol and quercetin also increased AMPK phosphorylation. None of the tested compounds (low or high glucose, pyruvate, and resveratrol) significantly altered the AMP/ATP ratio. Collectively, these findings raise the possibility that glucose-induced changes in AMPK are linked to alterations in SIRT1 abundance and activity and possibly cellular redox state.
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PMID:Concurrent regulation of AMP-activated protein kinase and SIRT1 in mammalian cells. 1907 Oct 85

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

Transcription of human immunodeficiency virus (HIV-1) is activated by viral Tat protein which regulates HIV-long terminal repeat (LTR) transcription and elongation. HIV-1 Tat protein is a substrate for the deacetylase activity of sirtuin 1 (SIRT1). Here we investigate the signaling pathway involved in Tat-induced HIV-1 transactivation through SIRT1. Western blot analysis showed a significant reduction in AMPK activation and downstream acetyl-CoA carboxylase (ACC) activation in response to Tat treatment. NAD(+) levels and SIRT1 activity were also decreased with Tat treatment. SIRT1 activator resveratrol reversed Tat-mediated reduction in AMPK activation and downstream ACC activation; while SIRT1 inhibitor nicotinamide or knockdown of SIRT1 by siRNA potentiated Tat-mediated reduction in AMPK activation and downstream ACC activation. Consistent with this association, AMPK activator AICAR as well as resveratrol inhibited Tat-induced HIV-1 transactivation. On the contrary, AMPK inhibitor compound C, knockdown of AMPK by siRNA as well as nicotinamide or knockdown of SIRT1 by siRNA potentiated Tat-induced HIV-1 transactivation. Collectively, our data provide new insights into understanding of the molecular mechanisms of Tat-regulated transcription, suggesting that targeting SIRT1-AMPK pathway could serve as a new target for the development of new anti HIV-1 agents.
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PMID:SIRT1 regulates Tat-induced HIV-1 transactivation through activating AMP-activated protein kinase. 1972 90


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