High Rates of Fatty Acid Oxidation during Reperfusion of Ischemic Hearts Are Associated with a Decrease in Malonyl-CoA Levels Due to an Increase in 5’-AMP-activated Protein Kinase Inhibition of Acetyl-CoA Carboxylase

Kudo, Naomi; Barr, Amy; Barr, Rick L.; Desai, Snehal; Lopaschuk, Gary D.

doi:10.1074/jbc.270.29.17513

Cited by 542 publications

(435 citation statements)

References 51 publications

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“…Deprivation of oxygen (hypoxia) is another stress that can limit catabolism, thus causing increases in AMP: ATP and AMPK activation. This occurs, for example, in cardiac muscle in response to ischaemia, an interruption in the blood supply (21)(22)(23) . Similar to what has just been described for hypoglycaemia, in most cells the oxygen tension has to drop to pathologically low levels (such as occurs during ischaemia) before AMPK is activated.…”

Section: Activation Of Mammalian Amp-activated Protein Kinase By Metamentioning

confidence: 99%

Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism

Hardie

2010

Proc. Nutr. Soc.

118

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The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status, and a regulator of energy balance at both the cellular and whole body levels. Although ubiquitously expressed, its function is best understood in skeletal muscle. AMPK contains sites that reversibly bind AMP or ATP, with an increase in cellular AMP :ATP ratio (signalling a fall in cellular energy status) switching on the kinase. In muscle, AMPK activation is therefore triggered by sustained contraction, and appears to be particularly important in the metabolic changes that occur in the transition from resistance to endurance exercise. Once activated, AMPK switches on catabolic processes that generate ATP, while switching off energy-requiring processes not essential in the short term. Thus, it acutely activates glucose uptake (by promoting translocation of the transporter GLUT4 to the membrane) and fatty acid oxidation, while switching off glycogen synthesis and protein synthesis (the later via inactivation of the mammalian target-ofrapamycin pathway). Prolonged AMPK activation also causes some of the chronic adaptations to endurance exercise, such as increased GLUT4 expression and mitochondrial biogenesis. AMPK contains a glycogen-binding domain that causes a sub-fraction to bind to the surface of the glycogen particle, and it can inhibit glycogen synthesis by phosphorylating glycogen synthase. We have shown that AMPK is inhibited by exposed non-reducing ends in glycogen. We are working on the hypothesis that this ensures that glycogen synthesis is rapidly activated when glycogen becomes depleted after exercise, but is switched off again as soon as glycogen stores are replenished. Muscle: Exercise: Type 2 diabetes: NutraceuticalsAnimal cells take up fuel molecules such as glucose or fatty acids, and oxidise them to CO 2 via the process of catabolism. Much of the energy released during this process is used to convert ADP to ATP, which can be likened to the chemicals in a rechargeable battery. Extending this analogy, catabolism charges up the battery by converting ADP to ATP, whereas most other cellular activities (e.g. growth, division, secretion and movement) require energy and are driven by the conversion of ATP back to ADP, thus draining the battery. Just as machines that utilise rechargeable batteries (such as laptop computers or electric cars) require systems to monitor the state of the battery, cells require systems to monitor their ATP : ADP ratio and match the rates of uptake and consumption of carbon nutrients to the rate of ATP utilisation. The topic of this review is the AMP-activated protein kinase (AMPK), which is the major system responsible for achieving this task in eukaryotes. Researchers who wish to understand disorders of energy balance, such as obesity and type-2 diabetes, have been particularly interested in the system. Protein kinases, including AMPK, are signalling enzymes that modify the function of target proteins by transferring phosphate groups from ATP to side chains of specific amino acids, usually serine o...

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Section: Activation Of Mammalian Amp-activated Protein Kinase By Metamentioning

confidence: 99%

Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism

Hardie

2010

Proc. Nutr. Soc.

118

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“…2,3,39 Although overall oxidative rates during ischemia are limited by oxygen supply to the muscle, during and following ischemia, AMPK activation can lower cardiac malonyl-CoA levels, secondary to phosphorylation and inhibition of acetyl CoA carboxylase. 2,3 Unfortunately, in the presence of an ischemia-induced limitation of overall oxidative metabolism, the AMPK-dependent acceleration of fatty acid oxidation occurs at the expense of glucose oxidation, and has the potential to be detrimental in the setting of ischemia/reperfusion. 3 During reperfusion, a continued activation of AMPK also contributes to fatty acid oxidation providing the majority of ATP production during the critical period of reperfusion, again at the expense of glucose oxidation.…”

Section: Ampk Activation During Ischemia/reperfusionmentioning

confidence: 99%

“…Cardiac AMPK is rapidly activated during ischemia. [2][3][4][5][6][7][8][9][10] This activation of AMPK results in a stimulation of glucose uptake, glycolysis and fatty acid oxidation. 3,5,6,11,12 These metabolic effects can have both beneficial and harmful effects during ischemia and during reperfusion following ischemia.…”

Section: Introductionmentioning

confidence: 99%

AMP-activated protein kinase control of energy metabolism in the ischemic heart

Lopaschuk

2008

Int J Obes

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Myocardial ischemia produces an energy-deficient state in heart muscle, which if not corrected can lead to cardiomyocyte death. AMP-activated protein kinase (AMPK) is a key kinase that can increase energy production in the ischemic heart. During ischemia a rapid activation of AMPK occurs, resulting in an activation of both myocardial glucose uptake and glycolysis, as well as an increase in fatty acid oxidation. This activation of AMPK has the potential to increase energy production, thereby protecting the heart during ischemic stress. However, at clinically relevant high levels of fatty acids, ischemia-induced activation of AMPK also stimulates fatty acid oxidation during and following ischemia. This can contribute to ischemic injury secondary to an inhibition of glucose oxidation, which results in a decrease in cardiac efficiency. As a result, AMPK activation has the potential to be either beneficial or harmful in the ischemic heart.

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“…Hepatic ACC activity was determined as an index of the synthetic activity for lipogenesis. ACC activity was measured from 6% PEG 8000 (Sigma Chemical-Aldrich) fraction, as previously reported (9,33), and was expressed as nanomoles of malonyl-CoA produced per minute per milligram of protein (U). Hepatic GK activity (34,35) was determined as the first key step enabling glucose to enter glycolysis.…”

Section: Methodsmentioning

confidence: 99%

Neonatal Exposure to Oxidants Induces Later in Life a Metabolic Response Associated to a Phenotype of Energy Deficiency in an Animal Model of Total Parenteral Nutrition

et al. 2010

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Failure to protect total parenteral nutrition (TPN) from ambient light exacerbates the generation of peroxides, which affects blood glucose and plasma triacylglyceride (TG) in neonates. Based on the concept that the origin of adult diseases can be traced back to perinatal life, it was hypothesized that neonatal exposure to peroxides may affect energy availability later in life. Three-day-old guinea pigs, fitted with a jugular catheter, were fed regular chow (sham) Ϯ i. T he association between oxidative stress and characteristic features of the metabolic syndrome, such as diabetes, hypertension, and dyslipidemia, is well documented (1-6). Human (7) and animal studies (8,9) suggest that the origin of the metabolic syndrome can be traced back to perinatal life, a time when newborn infants are at greater risk of oxidative stress caused by weak antioxidant defenses (10 -12) or exposure to an oxidative environment or both (13-18). Several reports suggest that, in neonates, oxidative stress triggers the events that lead to programming of adult diseases (19 -22).Total parenteral nutrition (TPN) represents a source of oxidants in the form of peroxides that can be calibrated either by applying or not photoprotecting. The peroxides are derived from interactions between dissolved oxygen and electron donors such as lipid, amino acid, or ascorbic acid (23,24). The reaction is catalyzed by photoexcited riboflavin (24). Therefore, the main active agents participating in the generation of peroxides in TPN are ambient light [(ϩ)L] and multivitamin preparations (MVP) (23,24). Photoprotection [(Ϫ)L] of TPN reduces the levels of peroxides by close to 50% (23,25,26). Absence of photoprotection of TPN is associated in preterm newborn infants with higher urinary peroxide concentrations (16), higher blood pressure in girl babies (15), and greater blood glucose and plasma triacylglycerol concentrations (13). Hence, peroxides contaminating TPN solutions are not completely quenched by newborns infants and are thought to be an agent initiating metabolic perturbations. We questioned whether these peroxides are linked to metabolic consequences later in life.Based on the concept that neonatal oxidative stress may interfere with metabolic programming (27), we hypothesized that neonatal exposure to peroxides such as those generated in solutions of parenteral nutrition, induces a permanent modification in lipid and glucose metabolism especially lipogenesis and/or glycolysis. Perturbations in lipid and glucose metabolism, which are fuels for energy production, could have longterm consequences on growth and physical activity, thereby affecting global development. The aim of this study was to measure in adult guinea pigs metabolic responses and spontaneous physical activity after a brief neonatal exposure to i.v. oxidant molecules limited to the first wk of life. A second objective was to assess if these modifications were related to the infusion of peroxides. MATERIALS AND METHODSExperimental design. The metabolic response and the levels...

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High Rates of Fatty Acid Oxidation during Reperfusion of Ischemic Hearts Are Associated with a Decrease in Malonyl-CoA Levels Due to an Increase in 5’-AMP-activated Protein Kinase Inhibition of Acetyl-CoA Carboxylase

Cited by 542 publications

References 51 publications

Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism

Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism

AMP-activated protein kinase control of energy metabolism in the ischemic heart

Neonatal Exposure to Oxidants Induces Later in Life a Metabolic Response Associated to a Phenotype of Energy Deficiency in an Animal Model of Total Parenteral Nutrition

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