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

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

The possible role of the AMP-activated protein kinase (AMPK), a highly conserved stress-activated kinase, in the regulation of ketone body production by astrocytes was studied. AMPK activity in rat cortical astrocytes was three times higher than in rat cortical neurons. AMPK in astrocytes was shown to be functionally active. Thus, incubation of astrocytes with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a cell-permeable activator of AMPK, stimulated both ketogenesis from palmitate and carnitine palmitoyltransferase I. This was concomitant to a decrease of intracellular malonyl-CoA levels and an inhibition of acetyl-CoA carboxylase/fatty acid synthesis and 3-hydroxy-3-methylglutaryl-CoA reductase/cholesterol synthesis. Moreover, in microdialysis experiments AICAR was shown to stimulate brain ketogenesis markedly. The effect of chemical hypoxia on AMPK and the ketogenic pathway was studied subsequently. Incubation of astrocytes with azide led to a remarkable drop of fatty acid beta-oxidation. However, activation of AMPK during hypoxia compensated the depression of beta-oxidation, thereby sustaining ketone body production. This effect seemed to rely on the cascade hypoxia --> increase of the AMP/ATP ratio --> AMPK stimulation --> acetyl-CoA carboxylase inhibition --> decrease of malonyl-CoA concentration --> carnitine palmitoyltransferase I deinhibition --> enhanced ketogenesis. Furthermore, incubation of neurons with azide blunted lactate oxidation, but not 3-hydroxybutyrate oxidation. Results show that (a) AMPK plays an active role in the regulation of ketone body production by astrocytes, and (b) ketone bodies produced by astrocytes during hypoxia might be a substrate for neuronal oxidative metabolism.
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PMID:The AMP-activated protein kinase is involved in the regulation of ketone body production by astrocytes. 1050 Dec 15

Alterations in the concentration of malonyl-CoA, an inhibitor of carnitine palmitoyltransferase I, have been linked to the regulation of fatty acid oxidation in skeletal muscle. During contraction decreases in muscle malonyl-CoA concentration have been related to activation of AMP-activated protein kinase (AMPK), which phosphorylates and inhibits acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in malonyl-CoA formation. We report here that the activity of malonyl-CoA decarboxylase (MCD) is increased in contracting muscle. Using either immunopurified enzyme or enzyme partially purified by (NH(4))(2)SO(4) precipitation, 2-3-fold increases in the V(max) of MCD and a 40% decrease in its K(m) for malonyl-CoA (190 versus 119 micrometer) were observed in rat gastrocnemius muscle after 5 min of contraction, induced by electrical stimulation of the sciatic nerve. The increase in MCD activity was markedly diminished when immunopurified enzyme was treated with protein phosphatase 2A or when phosphatase inhibitors were omitted from the homogenizing solution and assay mixture. Incubation of extensor digitorum longus muscle for 1 h with 2 mm 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside, a cell-permeable activator of AMPK, increased MCD activity 2-fold. Here, too, addition of protein phosphatase 2A to the immunopellets reversed the increase of MCD activity. The results strongly suggest that activation of AMPK during muscle contraction leads to phosphorylation of MCD and an increase in its activity. They also suggest a dual control of malonyl-CoA concentration by ACC and MCD, via AMPK, during exercise.
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PMID:Activation of malonyl-CoA decarboxylase in rat skeletal muscle by contraction and the AMP-activated protein kinase activator 5-aminoimidazole-4-carboxamide-1-beta -D-ribofuranoside. 1085 20

We tested for regulation of uncoupling protein 2 (UCP-2) in beta-cells in response to fatty acids and glucose. A 48-h culture with oleate (0.2 mM) at 5.5 or 11 mM glucose increased UCP-2 mRNA by 30-60% in INS-1 cells and in rat pancreatic islets. In contrast, oleate was ineffective after coculture at 27 mM glucose, P < 0.05 for difference 5.5 vs. 27 mM glucose. Also, culture with palmitate (0.1 mM) stimulated UCP-2 expression at 5.5 and 11 mM, but not at 27 mM glucose. Glucose per se failed to affect UCP-2 mRNA. Oxidation of [1-(14)C] oleate was increased by culture with oleate; however, this increase was attenuated by glucose during coculture, P < 0.05 for coculture at 5.5 vs. 27 mM glucose. Culture with aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, an activator of AMP-activated protein kinase, decreased cellular triglycerides, increased postculture [1-(14)C] oleate oxidation, and increased UCP-2 mRNA. Etomoxir, an inhibitor of carnitine palmitoyltransferase I, decreased the oleate-induced increase in UCP-2 mRNA. Rosiglitazone, a peroxisome proliferator-activated receptor gamma ligand, affected neither UCP-2 mRNA nor [1-(14)C] oleate oxidation. Antioxidants (vitamin E and sodium selenite) did not affect oleate-induced UCP-2 mRNA. We conclude that: 1) UCP-2 mRNA is induced by fatty acid oxidation in beta-cells; and 2) glucose exerts a modulating effect that is coupled to inhibition of fatty acid oxidation
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PMID:Induction of uncoupling protein 2 mRNA in beta-cells is stimulated by oxidation of fatty acids but not by nutrient oversupply. 1189 94

Diverse mechanisms of action have been proposed for 5-iodotubercidin, although it is widely used as an adenosine kinase inhibitor that consequently interferes with the metabolism of adenosine and adenine nucleotides. Incubation of rat hepatocytes with iodotubercidin produced important effects on lipid metabolism. (i) Both acetyl-CoA carboxylase and fatty acid synthesis de novo were inhibited in parallel by iodotubercidin, with no change in the activity of fatty acid synthase. The inhibition of both activities showed a comparable dependence on iodotubercidin concentration and was accompanied by a similar decrease (about 60%) in the intracellular malonyl-CoA concentration. (ii) Iodotubercidin stimulated palmitate oxidation, although octanoate oxidation was unaffected. However, this effect can be attributed to the decrease of malonyl-CoA concentration and the concomitant relief of the inhibition of carnitine palmitoyltransferase I, because the activity of this enzyme was found unaltered when determined in cells permeabilized with digitonin. (iii) Iodotubercidin also inhibited cholesterol synthesis de novo. Results, thus, indicate that iodotubercidin increases fatty acid oxidation activity of the liver at the expense of lipogenesis, and we suggest that these effects on fatty acid metabolism are mediated by the inhibition of acetyl-CoA carboxylase, probably due to a more than twice increase in the AMP/ATP ratio and the concomitant stimulation of the AMP-activated protein kinase.
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PMID:Effects of 5-iodotubercidin on hepatic fatty acid metabolism mediated by the inhibition of acetyl-CoA carboxylase. 1209 76

The accumulation of intracellular triacylglycerol (TG) is highly correlated with muscle insulin resistance. However, it is controversial whether the accumulation of TG is the result of increased fatty acid supply, decreased fatty acid oxidation, or both. Because abnormal fatty acid metabolism is a key contributor to the pathogenesis of diabetes-related cardiovascular dysfunction, we examined fatty acid and glucose metabolism in hearts of insulin-resistant JCR:LA-cp rats. Isolated working hearts from insulin-resistant rats had glycolytic rates that were reduced to 50% of lean control levels (P < 0.05). Cardiac TG content was increased by 50% (P < 0.05) in the insulin-resistant rats, but palmitate oxidation rates remained similar between the insulin-resistant and lean control rats. However, plasma fatty acids and TG levels, as well as cardiac fatty acid-binding protein (FABP) expression, were significantly increased in the insulin-resistant rats. AMP-activated protein kinase (AMPK) plays a major role in the regulation of cardiac fatty acid and glucose metabolism. When activated, AMPK increases fatty acid oxidation by inhibiting acetyl-CoA carboxylase (ACC) and reducing malonyl-CoA levels, and it decreases TG content by inhibiting glycerol-3-phosphate acyltransferase (GPAT), the rate-limiting step in TG synthesis. The activation of AMPK also stimulates cardiac glucose uptake and glycolysis. We thus investigated whether a decrease in AMPK activity was responsible for the reduced cardiac glycolysis and increased TG content in the insulin-resistant rats. However, we found no significant difference in AMPK activity. We also found no significant difference in various established downstream targets of AMPK: ACC activity, malonyl-CoA levels, carnitine palmitoyltransferase I activity, or GPAT activity. We conclude that hearts from insulin-resistant JCR:LA-cp rats accumulate substantial TG as a result of increased fatty acid supply rather than from reduced fatty acid oxidation. Furthermore, the accumulation of cardiac TG is associated with a reduction in insulin-stimulated glucose metabolism.
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PMID:Potential mechanisms and consequences of cardiac triacylglycerol accumulation in insulin-resistant rats. 1246 81

CPT I (outer membrane carnitine palmitoyltransferase I) is a crucial enzyme in myocardial substrate selection. Two isoforms exist in the heart, the liver (L-) and muscle (M-) isoforms, which have different kinetic characteristics and alter in relative amounts during the neonatal/weaning/adult transition. CPT I is a point for control and regulation of fatty acid oxidation via modulation of its activity by malonyl-CoA, the concentration of which is set by acetyl-CoA carboxylase, AMP-activated protein kinase and malonyl-CoA decarboxylase in response to, for example, alterations in glucose supply. Systemic inflammatory responses and sepsis lead to myocardial dysfunction as part of multiple system organ failure. We have shown that: (i) myocardial CPT I activity is inhibited during neonatal sepsis; (ii) on the basis of inhibitor studies this inhibition appears to be of M-CPT I rather than L-CPT I; (iii) nitration of M-CPT I occurs, probably by peroxynitrite, and this may be responsible for the decrease in CPT I activity; (iv) myocardial CPT I activity is also inhibited in another model of systemic inflammatory response, namely intestinal ischaemia/reperfusion injury, but this can prevented by whole-body moderate hypothermia. Inhibition of M-CPT I would be predicted to alter myocardial substrate selection but there are several questions that remain to be answered.
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PMID:Myocardial carnitine palmitoyltransferase I as a target for oxidative modification in inflammation and sepsis. 1464 Oct 11

Stearoyl-CoA desaturase (SCD) has recently been shown to be a critical control point of lipid partitioning and body weight regulation. Lack of SCD1 function significantly increases insulin sensitivity in skeletal muscles and corrects the hypometabolic phenotype of leptin-deficient ob/ob mice, indicating the direct antilipotoxic action of SCD1 deficiency. The mechanism underlying the metabolic effects of SCD1 mutation is currently unknown. Here we show that SCD1 deficiency reduced the total ceramide content in oxidative skeletal muscles (soleus and red gastrocnemius) by approximately 40%. The mRNA levels and activity of serine palmitoyltransferase (SPT), a key enzyme in ceramide synthesis, as well as the incorporation of [14C]palmitate into ceramide were decreased by approximately 50% in red muscles of SCD1-/- mice. The content of fatty acyl-CoAs, which contribute to de novo ceramide synthesis, was also reduced. The activity and mRNA levels of carnitine palmitoyltransferase I (CPT I) and the rate of beta-oxidation were increased in oxidative muscles of SCD1-/- mice. Furthermore, SCD1 deficiency increased phosphorylation of AMP-activated protein kinase (AMPK), suggesting that AMPK activation may be partially responsible for the increased fatty acid oxidation and decreased ceramide synthesis in red muscles of SCD1-/- mice. SCD1 deficiency also reduced SPT activity and ceramide content and increased AMPK phosphorylation and CPT I activity in muscles of ob/ob mice. Taken together, these results indicate that SCD1 deficiency reduces ceramide synthesis by decreasing SPT expression and increasing the rate of beta-oxidation in oxidative muscles.
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PMID:Stearoyl-CoA desaturase-1 deficiency reduces ceramide synthesis by downregulating serine palmitoyltransferase and increasing beta-oxidation in skeletal muscle. 1556 49

Myocardial fatty acid oxidation is regulated by carnitine palmitoyltransferase I (CPT I), which is inhibited by malonyl-CoA. Increased cardiac power causes a fall in malonyl-CoA content and accelerated fatty acid oxidation; however, the mechanism for the decrease in malonyl-CoA is unclear. Malonyl-CoA is formed by acetyl-CoA carboxylase (ACC) and degraded by malonyl-CoA decarboxylase (MCD); thus a fall in malonyl-CoA could be due to activation of MCD, inhibition of ACC, or both. This study assessed the effects of increased cardiac power on malonyl-CoA content and ACC and MCD activities. Anesthetized pigs were studied under control conditions and during increased cardiac power in response to dobutamine infusion and aortic constriction alone, under hyperglycemic conditions, or with the CPT I inhibitor oxfenicine. An increase in cardiac power was accompanied by increased myocardial O(2) consumption, decreased malonyl-CoA concentration, and increased fatty acid oxidation. There were no differences among groups in activity of ACC or AMP-activated protein kinase (AMPK), which physiologically inhibits ACC. There also were no differences in V(max) or K(m) of MCD. Previous studies have demonstrated that AMPK can be inhibited by protein kinase B (PKB); however, PKB was activated by dobutamine and the elevated insulin that accompanied hyperglycemia, but there was no effect on AMPK activity. In conclusion, the fall in malonyl-CoA and increase in fatty acid oxidation that occur with increased cardiac work were not due to inhibition of ACC or activation of MCD, suggesting alternative regulatory mechanisms for the work-induced decrease in malonyl-CoA concentration.
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PMID:Regulation of cardiac malonyl-CoA content and fatty acid oxidation during increased cardiac power. 1582 Oct 35


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