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)

Incubation of rat hepatocytes with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), an activator of the 5'-AMP-activated protein kinase (AMPK), produced a twofold stimulation of palmitate oxidation and of the activity of carnitine palmitoyltransferase I (CPT-I), together with a profound decrease of the activity of acetyl-CoA carboxylase and of the intracellular level of malonyl-CoA. AICAR-induced CPT-I stimulation progressively blunted with time after cell permeabilization, pointing to reversal of conformational constraints of the enzyme in control cells due to the permeabilization-triggered dilution of intracellular malonyl-CoA. The stimulation stabilized at a steady 20-25%. This 20-25% increase in CPT-I activity survived upon complete removal of malonyl-CoA from the permeabilized cells, indicating that it was not dependent on the malonyl-CoA concentration of the cell. This malonyl-CoA-independent activation of CPT-I was not evident when mitochondria were isolated for assay of enzyme activity or when cells were disrupted by vigorous sonication. In addition, the microtubule stabilizer taxol prevented the malonyl-CoA-independent stimulation of CPT-I induced by AICAR. Hence, stimulation of hepatic fatty acid oxidation by AMPK seems to rely on the activation of CPT-I by two different mechanisms: deinhibition of CPT-I induced by depletion of intracellular malonyl-CoA levels and malonyl-CoA-independent stimulation of CPT-I, which might involve modulation of interactions between CPT-I and cytoskeletal components.
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PMID:Control of hepatic fatty acid oxidation by 5'-AMP-activated protein kinase involves a malonyl-CoA-dependent and a malonyl-CoA-independent mechanism. 901 10

As muscle goes from a resting state to exercise, the following sequence of events occurs (Figure 5.5): (1) The rise in AMP accompanying contraction allosterically activates AMPK and an AMPK kinase; (2) The activated AMPK kinase phosphorylates and further activates AMPK; (3) The activated AMPK phosphorylates and inactivates ACC; and (4) The consequent decline in malonyl-CoA (product of ACC reaction) relieves inhibition of CPT-1 and allows an increased rate of fatty acid oxidation when fatty acids become available.
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PMID:Malonyl-CoA--regulator of fatty acid oxidation in muscle during exercise. 969 87

The activity of hepatic carnitine palmitoyltransferase I (CPT-I) may be modulated by interactions with cytoskeletal components [Velasco et al. (1998) J. Biol. Chem. 273, 21497-21504]. We have studied whether the AMP-activated protein kinase (AMPK) is involved in this process. AMPK stimulated CPT-I in permeabilized hepatocytes but not in isolated liver mitochondria. In addition, AMPK abrogated the inhibition of CPT-I of isolated mitochondria induced by a cytoskeletal fraction. These two effects of AMPK were not evident when the kinase was inactivated by pretreatment with protein phosphatase 2C. Cytokeratins 8 and 18 were phosphorylated by AMPK in vitro and by incubation of intact hepatocytes with 5-aminoimidazole-4-carboxamide ribonucleoside, a cell-permeable activator of AMPK. These results provide the first evidence that AMPK stimulates CPT-I by direct phosphorylation of cytoskeletal components.
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PMID:Evidence that the AMP-activated protein kinase stimulates rat liver carnitine palmitoyltransferase I by phosphorylating cytoskeletal components. 984 45

We have identified a novel omega-hydroxy-alkanedicarboxylic acid, ESP 55016, that favorably alters serum lipid variables in obese female Zucker (fa/fa) rats. ESP 55016 reduced serum non-HDL-cholesterol (non-HDL-C), triglyceride, and nonesterified fatty acid levels while increasing serum HDL-C and beta-hydroxybutyrate levels in a dose-dependent manner. ESP 55016 reduced fasting serum insulin and glucose levels while also suppressing weight gain. In primary rat hepatocytes, ESP 55016 increased the oxidation of [(14)C]palmitate in a dose- and carnitine palmitoyl transferase-I (CPT-I)-dependent manner. Furthermore, in primary rat hepatocytes and in vivo, ESP 55016 inhibited fatty acid and sterol synthesis. The "dual inhibitor" activity of ESP 55016 was unlikely attributable to the activation of the AMP-activated protein kinase (AMPK) pathway because AMPK and acetyl-CoA carboxylase (ACC) phosphorylation states as well as ACC activity were not altered by ESP 55016. Further studies indicated the conversion of ESP 55016 to a CoA derivative in vivo. ESP 55016-CoA markedly inhibited the activity of partially purified ACC. The activity of partially purified HMG-CoA reductase was not altered by the xenobiotic-CoA. These data suggest that ESP 55016-CoA favorably alters lipid metabolism in a model of diabetic dyslipidemia in part by initially inhibiting fatty acid and sterol synthesis plus enhancing the oxidation of fatty acids through the ACC/malonyl-CoA/CPT-I regulatory axis.
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PMID:Effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndrome. 1510 84

Stearoyl-CoA desaturase catalyzes the rate-limiting step in the biosynthesis of monounsaturated fatty acids, which are required for normal rates of synthesis of triglycerides, cholesterol esters, and phospholipids. Mice with a targeted disruption of the stearoyl-CoA desaturase 1 (SCD1) isoform are protected against diet and leptin deficiency-induced adiposity, have increased energy expenditure, and have up-regulated expression of hepatic genes encoding enzymes of fatty acid beta-oxidation. Because peroxisome proliferator-activated receptor-alpha (PPARalpha) is a key transcription factor that induces the transcription of fatty acid beta-oxidation and thermogenic genes, we hypothesized that the increased fatty acid oxidation observed in SCD1 deficiency is dependent on activation of the PPARalpha pathway. Here we show that mice nullizygous for SCD1 and PPARalpha are still protected against adiposity, have increased energy expenditure, and maintain high expression of PPARalpha target genes in the liver and brown adipose tissue. The SCD1 deficiency rescued hepatic steatosis of the PPARalpha(-/-) mice. The SCD1 mutation increased the phosphorylation of both AMP-activated protein kinase and acetyl-CoA carboxylase, thereby increasing CPT activity and stimulating the oxidation of liver palmitoyl-CoA in the PPARalpha null mice. The findings indicate that the reduced adiposity, reduced liver steatosis, increased energy expenditure, and increased expression of PPARalpha target genes associated with SCD1 deficiency are independent of activation of the PPARalpha pathway.
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PMID:Reduced adiposity and liver steatosis by stearoyl-CoA desaturase deficiency are independent of peroxisome proliferator-activated receptor-alpha. 1518 Sep 99

Malonyl-CoA, a potent inhibitor of carnitine pamitoyl transferase-I (CPT-I), plays a pivotal role in fuel selection in cardiac muscle. Malonyl-CoA decarboxylase (MCD) catalyzes the degradation of malonyl-CoA, removes a potent allosteric inhibition on CPT-I and thereby increases fatty acid oxidation in the heart. Although MCD has several Ser/Thr phosphorylation sites, whether it is regulated by AMP-activated protein kinase (AMPK) has been controversial. We therefore overexpressed MCD (Ad.MCD) and constitutively active AMPK (Ad.CA-AMPK) in H9c2 cells, using an adenoviral gene delivery approach in order to examine if MCD is regulated by AMPK. Cells infected with Ad.CA-AMPK demonstrated a fourfold increase in AMPK activity as compared with control cells expressing green fluorescent protein (Ad.GFP). MCD activity increased 40- to 50-fold in Ad.MCD + Ad.GFP cells when compared with Ad.GFP control. Co-expressing AMPK with MCD further augmented MCD expression and activity in Ad.MCD + Ad.CA-AMPK cells compared with the Ad.MCD + Ad.GFP control. Subcellular fractionation further revealed that 54.7 kDa isoform of MCD expression was significantly higher in cytosolic fractions of Ad.MCD + Ad.CA-AMPK cells than of the Ad.MCD +Ad.GFP control. However, the MCD activities in cytosolic fractions were not different between the two groups. Interestingly, in the mitochondrial fractions, MCD activity significantly increased in Ad.MCD + Ad.CA-AMPK cells when compared with Ad.MCD + Ad.GFP cells. Using phosphoserine and phosphothreonine antibodies, no phosphorylation of MCD by AMPK was observed. The increase in MCD activity in mitochondria-rich fractions of Ad.MCD + Ad.CA-AMPK cells was accompanied by an increase in the level of the 50.7 kDa isoform of MCD protein in the mitochondria. This differential regulation of MCD expression and activity in the mitochondria by AMPK may potentially regulate malonyl-CoA levels at sites nearby CPT-I on the mitochondria.
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PMID:Malonyl-CoA decarboxylase (MCD) is differentially regulated in subcellular compartments by 5'AMP-activated protein kinase (AMPK). Studies using H9c2 cells overexpressing MCD and AMPK by adenoviral gene transfer technique. 1520 48

Activation of the oncogenic kinase Akt stimulates glucose uptake and metabolism in cancer cells and renders these cells susceptible to death in response to glucose withdrawal. Here we show that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) reverses the sensitivity of Akt-expressing glioblastoma cells to glucose deprivation. AICAR's protection depends on the activation of AMPK, as expression of a dominant-negative form of AMPK abolished this effect. AMPK is a cellular energy sensor whose activation can both block anabolic pathways such as protein synthesis and activate catabolic reactions such as fatty acid oxidation to maintain cellular bioenergetics. While rapamycin treatment mimicked the effect of AICAR on inhibiting markers of cap-dependent translation, it failed to protect Akt-expressing cells from death upon glucose withdrawal. Compared to control cells, Akt-expressing cells were impaired in the ability to induce fatty acid oxidation in response to glucose deprivation unless stimulated with AICAR. Stimulation of fatty acid oxidation was sufficient to maintain cell survival as activation of fatty acid oxidation with bezafibrate also protected Akt-expressing cells from glucose withdrawal-induced death. Conversely, treatment with a CPT-1 inhibitor to block fatty acid import into mitochondria prevented AICAR from stimulating fatty acid oxidation and promoting cell survival in the absence of glucose. Finally, cell survival did not require reversal of Akt's effects on either protein translation or lipid synthesis as the addition of the cell penetrant oxidizable substrate methyl-pyruvate was sufficient to maintain survival of Akt-expressing cells deprived of glucose. Together, these data suggest that activation of Akt blocks the ability of cancer cells to metabolize nonglycolytic bioenergetic substrates, leading to glucose addiction.
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PMID:The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid beta-oxidation. 1580 54

Although metabolites and energy balance have long been known to play roles in the regulation of food intake, the potential role of fatty acid metabolism in this process has been considered only recently. Fatty acid synthase (FAS) catalyzes the condensation of acetyl-CoA and malonyl-CoA to generate long-chain fatty acids in the cytoplasm, while the breakdown of fatty acids (beta-oxidation) occurs in mitochondria and is regulated by carnitine palmitoyltransferase-1 (CPT-1), the rate-limiting step for the entry of fatty acids into the mitochondria. Inhibition of FAS using cerulenin or synthetic FAS inhibitors such as C75 reduces food intake and induces profound reversible weight loss. Subsequent studies reveal that C75 also stimulates CPT-1 and increases beta-oxidation. Hypotheses as to the mechanisms by which C75 and cerulenin mediate their effects have been proposed. Centrally, these compounds alter the expression profiles of feeding-related neuropeptides, often inhibiting the expression of orexigenic peptides. Whether through centrally mediated or peripheral mechanisms, C75 also increases energy consumption, which contributes to weight loss. In vitro and in vivo studies demonstrate that at least part of C75's effects is mediated by modulation of AMP-activated protein kinase (AMPK), a known peripheral energy-sensing kinase. Collectively, these data suggest a role for fatty acid metabolism in the perception and regulation of energy balance.
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PMID:Fatty acid metabolism as a target for obesity treatment. 1587 85

Extracellular adenosine reduced viability of RCR-1 rat astrocytoma cells in a dose (0.3-10mM)- and treatment time (24-72h)-dependent manner. In the apoptosis assay using propidium iodide (PI) and annexin V, treatment with adenosine (1mM) for 72h increased the population of PI-negative/annexin V-positive cells, that is related to early apoptosis, and that of PI-positive/annexin V-positive cells, that is related to late apoptosis/secondary necrosis. In addition, nuclei of cells treated with adenosine (1mM) for 72h were reactive to an antibody against single-stranded DNA. Adenosine activated caspase-3, -8 and -9, but mitochondrial membrane potentials were not affected. Adenosine-induced RCR-1 cell death was significantly inhibited by 8-CPT, an antagonist of A(1) adenosine receptors, and forskolin, an adenylate cyclase activator. SQ22536, an adenylate cyclase inhibitor, alternatively, exhibited an effect similar to adenosine. CHA, an agonist of A(1) adenosine receptors, activated caspase-3 and -9, but not caspase-8. Adenosine-induced cytotoxicity of RCR-1 cells was also significantly inhibited by dipyridamole, an inhibitor of adenosine transporter, and AMDA, an inhibitor of adenosine kinase. AICAR, an activator of AMP-activated protein kinase (AMPK), reduced RCR-1 cell viability, but synergistic effect was not obtained with co-treatment with adenosine and AICAR. AICAR activated caspase-3 and -9, but not caspase-8. An additive inhibition was found in the co-presence of 8-CPT and dipyridamole. Extracellular adenosine, thus, appears to activate caspase-9 followed by the effector caspase, caspase-3, at least via two independent pathways linked to A(1) adenosine receptor-mediated adenylate cyclase inhibition and adenosine uptake into cells/conversion to AMP/activation of AMPK, possibly regardless of mitochondrial damage, thereby leading to RCR-1 cell death, dominantly by apoptosis. Moreover, caspase-8 activation could again contribute to adenosine-induced cytotoxicity, although the underlying mechanism is currently unknown. Collectively, the results of the present study may represent a new pathway for caspase activation relevant to diverse adenosine signals in cell death.
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PMID:A(1) adenosine receptor signal and AMPK involving caspase-9/-3 activation are responsible for adenosine-induced RCR-1 astrocytoma cell death. 1646 85

Peroxisome proliferator-activated receptor-delta (PPARdelta) activation enhances skeletal muscle fatty acid oxidation and improves whole body glucose homeostasis and insulin sensitivity. Recently, GW501516, a selective PPARdelta agonist, was reported to increase glucose uptake in human skeletal myotubes by an AMPK-dependent mechanism that may contribute to the improved glucose tolerance. Here, we demonstrate that whilst GW501516 increases expression of PGC-1alpha and CPT-1 and stimulates fatty-acid oxidation in L6 myotubes, it fails to enhance insulin sensitivity, AMPK activity or glucose uptake and storage. Our findings exclude sarcolemmal glucose transport as a potential target for the therapeutic action of PPARdelta agonists in skeletal muscle.
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PMID:The PPARdelta agonist, GW501516, promotes fatty acid oxidation but has no direct effect on glucose utilisation or insulin sensitivity in rat L6 skeletal muscle cells. 1786 49


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