Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.27 (AMPK)
 6,299 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several links relate mitochondrial metabolism and type 2 diabetes or chronic hyperglycaemia. Among them, ATP synthesis by oxidative phosphorylation and cellular energy metabolism (ATP/ADP ratio), redox status and reactive oxygen species (ROS) production, membrane potential and substrate transport across the mitochondrial membrane are involved at various steps of the very complex network of glucose metabolism. Recently, the following findings (1) mitochondrial ROS production is central in the signalling pathway of harmful effects of hyperglycaemia, (2) AMPK activation is a major regulator of both glucose and lipid metabolism connected with cellular energy status, (3) hyperglycaemia by inhibiting glucose-6-phosphate dehydrogenase (G6PDH) by a cAMP mechanism plays a crucial role in NADPH/NADP ratio and thus in the pro-oxidant/anti-oxidant cellular status, have deeply changed our view of diabetes and related complications. It has been reported that metformin has many different cellular effects according to the experimental models and/or conditions. However, recent important findings may explain its unique efficacy in the treatment of hyperglycaemia- or insulin-resistance related complications. Metformin is a mild inhibitor of respiratory chain complex 1; it activates AMPK in several models, apparently independently of changes in the AMP-to-ATP ratio; it activates G6PDH in a model of high-fat related insulin resistance; and it has antioxidant properties by a mechanism (s), which is (are) not completely elucidated as yet. Although it is clear that metformin has non-mitochondrial effects, since it affects erythrocyte metabolism, the mitochondrial effects of metformin are probably crucial in explaining the various properties of this drug.
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PMID:Mitochondrial metabolism and type-2 diabetes: a specific target of metformin. 1450 5

Cyclic AMP responsive element (CRE)-binding protein (CREB) is known to activate transcription when its Ser133 is phosphorylated. Two independent investigations have suggested the presence of Ser133-independent activation. One study identified a kinase, salt-inducible kinase (SIK), which repressed CREB; the other isolated a novel CREB-specific coactivator, transducer of regulated CREB activity (TORC), which upregulated CREB activity. These two opposing signals are connected by the fact that SIK phosphorylates TORC and induces its nuclear export. Because LKB1 has been reported to be an upstream kinase of SIK, we used LKB1-defective HeLa cells to further elucidate TORC-dependent CREB activation. In the absence of LKB1, SIK was unable to phosphorylate TORC, which led to constitutive activation of CRE activity. Overexpression of LKB1 in HeLa cells improved the CRE-dependent transcription in a regulated manner. The inactivation of kinase cascades by 10 nm staurosporine in LKB1-positive HEK293 cells also induced unregulated, constitutively activated, CRE activity. Treatment with staurosporine completely inhibited SIK kinase activity without any significant effect on the phosphorylation level at the LKB1-phosphorylatable site in SIK or the activity of AMPK, another target of LKB1. Constitutive activation of CREB in LKB1-defective cells or in staurosporine-treated cells was not accompanied by CREB phosphorylation at Ser133. The results suggest that LKB1 and its downstream SIK play an important role in silencing CREB activity via the phosphorylation of TORC, and such silencing may be indispensable for the regulated activation of CREB.
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PMID:Silencing the constitutive active transcription factor CREB by the LKB1-SIK signaling cascade. 1681 1

Compensatory beta cell growth occurs in accordance to overweight and increasing insulin demands. The proliferative actions of insulin and insulin-like growth factors are mediated via the IRS-2-PI(3)K-Akt pathway of pleiotropic insulin signaling. However, sustained activation leads to negative feedback via the mTOR-induced proteasomal degradation of IRS-2. The proliferative actions of incretins and adipokines are mediated via other pathways that ultimately converge with the IRS-2-PI(3)K-Akt axis. The incretins GIP and GLP-1 increase IRS-2 levels in beta cells by acting via the cAMP-PKA pathway, whereas leptin inhibits PTEN activity via CK2-dependent pathways. By increasing PIP(3) availability the adipokine amplifies the magnitude as well as duration of factors acting via the IRS-2-PI(3)K-Akt pathway. Considering that AMPK prevents mTOR-induced degradation of IRS-2, we propose that adiponectin and leptin cooperatively achieve compensatory beta cell growth in accordance to adiposity. In conditions of overt obesity, when adiponectin levels are too low to provide sufficient IRS-2 levels, loss of compensatory beta cell growth may occur.
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PMID:Leptin and adiponectin regulate compensatory beta cell growth in accordance to overweight. 1709 72

CREB is a cAMP- and calcium-responsive transcriptional activator that is required for islet beta cell proliferation and survival. Glucose and incretin hormones elicit beta cell insulin secretion and promote synergistic CREB activity by inducing the nuclear relocalization of TORC2 (also known as Crtc2), a coactivator for CREB. In islet cells under basal conditions when CREB activity is low, TORC2 is phosphorylated and sequestered in the cytoplasm by 14-3-3 proteins. In response to feeding stimuli, TORC2 is dephosphorylated, enters the nucleus, and binds to CREB located at target gene promoters. The dephosphorylation of TORC2 at Ser-171 in response to cAMP is insufficient to account for the dynamics of TORC2 localization and CREB activity in islet cells. Here, we identify Ser-275 of TORC2 as a 14-3-3 binding site that is phosphorylated under low glucose conditions and which becomes dephosphorylated by calcineurin in response to glucose influx. Dephosphorylation of Ser-275 is essential for both glucose and cAMP-mediated activation of CREB in beta cells and islets. Using a cell-based screen of 180 human protein kinases, we identified MARK2, a member of the AMPK family of Ser/Thr kinases, as a Ser-275 kinase that blocks TORC2:CREB activity. Taken together, these data provide the mechanistic underpinning for how cAMP and glucose cooperatively promote a transcriptional program critical for islet cell survival, and identifies MARK2 as a potential target for diabetes treatment.
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PMID:Glucose controls CREB activity in islet cells via regulated phosphorylation of TORC2. 1862 18

Previous in vitro studies suggested that Cl(-) currents produced by the cystic fibrosis transmembrane conductance regulator (CFTR; ABCC7) are inhibited by the alpha1 isoform of the adenosine monophosphate (AMP)-stimulated kinase (AMPK). AMPK is a serine/threonine kinase that is activated during metabolic stress. It has been proposed as a potential mediator for transport-metabolism coupling in epithelial tissues. All previous studies have been performed in vitro and thus little is known about the regulation of Cl(-) secretion by AMPK in vivo. Using AMPKalpha1(-/-) mice and wild-type littermates, we demonstrate that phenformin, an activator of AMPK, strongly inhibits cAMP-activated Cl(-) secretion in mouse airways and colon, when examined in ex vivo in Ussing chamber recordings. However, phenformin was equally effective in AMPKalpha1(-/-) and wild-type animals, suggesting additional AMPK-independent action of phenformin. Phenformin inhibited CFTR Cl(-) conductance in basolaterally permeabilized colonic epithelium from AMPKalpha1(+/+) but not AMPKalpha1(-/-) mice. The inhibitor of AMPK compound C enhanced CFTR-mediated Cl(-) secretion in epithelial tissues of AMPKalpha1(-/-) mice, but not in wild-type littermates. There was no effect on Ca(2+)-mediated Cl(-) secretion, activated by adenosine triphosphate or carbachol. Moreover CFTR-dependent Cl(-) secretion was enhanced in the colon of AMPKalpha1(-/-) mice, as indicated in Ussing chamber ex vivo and rectal PD measurements in vivo. Taken together, these data suggest that epithelial Cl(-) secretion mediated by CFTR is controlled by AMPK in vivo.
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PMID:Regulation of Cl(-) secretion by AMPK in vivo. 1875 1

BeWo cells, derived from human choriocarcinoma, have been known to respond to forskolin or cAMP analogues by differentiating into multinucleated cells- like syncytiotrophoblasts on the surfaces of chorionic villi of the human placenta. In this study, we demonstrated that long-term treatment with forskolin enhances the tight junction (TJ) formation in human placental BeWo cells. Interestingly, AMPK activation and phosphorylation of acetyl-CoA carboxylase (ACC), a molecule downstream from AMPK, were induced by long-term incubation (>12h) with forskolin, despite not being induced by acute stimulation with forskolin. In addition, co-incubation with an AMPK inhibitor, compound C, as well as overexpression of an AMPK dominant negative mutant inhibited forskolin-induced TJ formation. Thus, although the molecular mechanism underlying AMPK activation via the forskolin stimulation is unclear, the TJ formation induced by forskolin is likely to be mediated by the AMPK pathway. Taking into consideration that TJs are present in the normal human placenta, this mechanism may be important for forming the placental barrier system between the fetal and maternal circulations.
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PMID:Long-term forskolin stimulation induces AMPK activation and thereby enhances tight junction formation in human placental trophoblast BeWo cells. 1895 Aug 55

AMPK (AMP-activated protein kinase) is a key regulator of cellular energy because of its capacity to detect changes in the concentration of AMP. Recent evidence, however, indicates the existence of alternative mechanisms of activation of this protein. Mitochondrial ROS (reactive oxygen species), generated as a result of the interaction between nitric oxide and mitochondrial cytochrome c oxidase, activate AMPKalpha1 in HUVECs (human umbilical-vein endothelial cells) at a low oxygen concentration (i.e. 3%). This activation is independent of changes in AMP. In the present study we show, using HUVECs in which AMPKalpha1 has been silenced, that this protein is responsible for the expression of genes involved in antioxidant defence, such as manganese superoxide dismutase, catalase, gamma-glutamylcysteine synthase and thioredoxin. Furthermore, peroxisome proliferator-activated-coactivator-1, cAMP-response-element-binding protein and Foxo3a (forkhead transcription factor 3a) are involved in this signalling pathway. In addition, we show that silencing AMPKalpha1 in cells results in a reduced mitochondrial and eNOS (endothelial NO synthase) content, reduced cell proliferation, increased accumulation of ROS and apoptosis. Thus AMPKalpha1 in HUVECs regulates both their mitochondrial content and their antioxidant defences. Pharmacological activation of AMPKalpha1 in the vascular endothelium may be beneficial in conditions such as metabolic syndrome, Type 2 diabetes and atherosclerosis, not only because of its bioenergetic effects but also because of its ability to counteract oxidative stress.
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PMID:AMPKalpha1 regulates the antioxidant status of vascular endothelial cells. 1944 39

In mammals, nicotinamide phosphoribosyltransferase (NAMPT) is responsible for the first and rate-limiting step in the conversion of nicotinamide to nicotinamide adenine dinucleotide (NAD+). NAD+ is an obligate cosubstrate for mammalian sirtuin-1 (SIRT1), a deacetylase that activates peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), which in turn can activate mitochondrial biogenesis. Given that mitochondrial biogenesis is activated by exercise, we hypothesized that exercise would increase NAMPT expression, as a potential mechanism leading to increased mitochondrial content in muscle. A cross-sectional analysis of human subjects showed that athletes had about a twofold higher skeletal muscle NAMPT protein expression compared with sedentary obese, nonobese, and type 2 diabetic subjects (P < 0.05). NAMPT protein correlated with mitochondrial content as estimated by complex III protein content (R(2) = 0.28, P < 0.01), MRS-measured maximal ATP synthesis (R(2) = 0.37, P = 0.002), and Vo(2max) (R(2) = 0.63, P < 0.0001). In an exercise intervention study, NAMPT protein increased by 127% in sedentary nonobese subjects after 3 wk of exercise training (P < 0.01). Treatment of primary human myotubes with forskolin, a cAMP signaling pathway activator, resulted in an approximately 2.5-fold increase in NAMPT protein expression, whereas treatment with ionomycin had no effect. Activation of AMPK via AICAR resulted in an approximately 3.4-fold increase in NAMPT mRNA (P < 0.05) as well as modest increases in NAMPT protein (P < 0.05) and mitochondrial content (P < 0.05). These results demonstrate that exercise increases skeletal muscle NAMPT expression and that NAMPT correlates with mitochondrial content. Further studies are necessary to elucidate the pathways regulating NAMPT as well as its downstream effects.
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PMID:Skeletal muscle NAMPT is induced by exercise in humans. 1988 95

NAD-dependent deacetylase SIRT1 is known to be activated by caloric restriction and is related to longevity. A natural polyphenolic compound resveratrol is also shown to increases SIRT1 activity and extends lifespan. However, the transcriptional regulation of SIRT1 gene has not completely examined in the context of metabolism. Thus, in this study, we characterized the 5' -flanking region of human SIRT1 gene. We first found that representative metabolic hormones and related factors (glucocorticoid, glucagon/cAMP, and insulin) did not show significant effect on SIRT1 gene transcription. PPARalpha and PPARgamma1 without/with their specific ligands did not have significant effect as well. In contrast, expression of PPARbeta/delta (PPARdelta markedly increased the 5' -promoter activity of SIRT1 gene, which was further amplified by the addition of GW501516, a selective PPARdelta agonist. Deletion/mutation mapping analyses failed to identify PPAR binding element but revealed the presence of canonical Sp1 binding site, which was conserved among species. The Sp1 site is functional, because Sp1 overexpresson significantly enhanced SIRT1 promoter activity, and the binding of Sp1 to the element was confirmed by EMSA and ChIP assays. Interestingly, specific Sp1 antagonist mithramycin completely abolished the PPARdelta-mediated induction of SIRT1 gene transcription. Altogether, our data suggest the predominant role of PPARdelta in the transcriptional regulation of SIRT1 gene. Furthermore, the effects of PPARdelta seem to be mediated by Sp1. We assume that, in vivo, starvation increases lipolysis-derived free fatty acid and activates PPARdelta and the resultant increase in SIRT1 expression, in addition to the activation by NAD and AMPK, facilitates the deacetylation of a variety of proteins involved in mitochondrial beta-oxidation pathway and cell survival.
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PMID:PPARbeta/delta regulates the human SIRT1 gene transcription via Sp1. 2016 Mar 99

PKA is an important mediator of signal transduction downstream of G-protein-coupled receptors and plays a key role in the regulation of metabolism and triglyceride storage. It is a ubiquitous cellular kinase that phosphorylates serine and threonine residues in response to cAMP. PKA consists of two regulatory subunits, RI and RII, that are activated by cAMP to release two catalytic subunits, Calpha and Cbeta. We have shown that C57/BL6J male mice lacking the regulatory RIIbeta subunit have extended lifespan and are resistant to age-related conditions including cardiac decline. In addition to being protected from diet-induced pathologies, PKA Cbeta null mutant mice are protected from age-related problems such as weight gain and enlarged livers, as well as cardiac dysfunction and hypertrophy. Several possible mechanisms for the age sparing effects of PKA inhibition are discussed including A kinase anchoring protein signaling, alterations in the beta-adrenergic pathway, and activation of AMPK. Since PKA is a major metabolic regulator of gene signaling, the human gene homologs are potential pharmacological targets for age-related conditions including heart disease associated with declining cardiac performance.
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PMID:Protein kinase A is a target for aging and the aging heart. 2044 93


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