Type 2 diabetes (T2D) increases the risk for diabetic cardiomyopathy and is characterized by diastolic dysfunction. Myocardial forkhead box O1 (FoxO1) activity is enhanced in T2D and upregulates pyruvate dehydrogenase (PDH) kinase 4 expression, which inhibits PDH activity, the rate-limiting enzyme of glucose oxidation.
Full Answer
Is inhibition of pyruvate dehydrogenase kinase A therapeutic strategy against cancer?
Inhibition of Pyruvate Dehydrogenase Kinase as a Therapeutic Strategy against Cancer Cancer cells alter their metabolism to support the uninterrupted supply of biosynthetic molecules required for continuous proliferation.
What is the role of pyruvate dehydrogenase complex in glucose metabolism?
In glucose metabolism, pyruvate dehydrogenase complex (PDC) mediates a major regulatory step, an irreversible reaction of oxidative decarboxylation of pyruvate to acetyl-CoA. Tight control of PDC is critical because it plays a key role in glucose disposal.
What increases the amount of pyruvate dehydrogenase kinase in rat heart?
Starvation increases the amount of pyruvate dehydrogenase kinase in several mammalian tissues. Arch Biochem Biophys. 2000;381:1–7. [PubMed] [Google Scholar] 18. Wu P, Sato J, Zhao Y, Jaskiewicz J, Popov KM, Harris RA. Starvation and diabetes increase the amount of pyruvate dehydrogenase kinase isoenzyme 4 in rat heart.
How does dexamethasone inhibit pyruvate dehydrogenase kinase-4 gene induction?
Protein kinase B-alpha inhibits human pyruvate dehydrogenase kinase-4 gene induction by dexamethasone through inactivation of FOXO transcription factors. Diabetes. 2004;53:899–910.
What happens when you inhibit pyruvate dehydrogenase?
By inhibiting its target enzyme PDH, PDK prevents the coupling of glycolysis to GO. Therefore glycolysis is completed in the cytoplasm, where pyruvate is metabolized further without being oxidized in the mitochondria. This metabolic shift is a fundamental response in most tissues under hypoxia.
What is an inhibitor of pyruvate dehydrogenase?
Dichloroacetate, an inhibitor of pyruvate dehydrogenase kinases, inhibits platelet aggregation and arterial thrombosis. Blood Adv.
What does pyruvate dehydrogenase kinase do?
Pyruvate dehydrogenase kinase (PDK) is a kinase that inactivates the pyruvate dehydrogenase enzyme complex through phosphorylation. By downregulating the activity of this complex, PDK decreases the oxidation of pyruvate in mitochondria and increases the conversion of pyruvate to lactate in the cytosol.
Does insulin inhibit pyruvate dehydrogenase?
Insulin indirectly stimulates glucose oxidation via increasing glucose uptake and subsequent glycolysis that increases pyruvate supply for mitochondrial glucose oxidation by the pyruvate dehydrogenase (PDH) complex, the rate-limiting enzyme of glucose oxidation.
Why does acetyl-CoA inhibit pyruvate dehydrogenase?
Absence of acetyl-CoA promotes inhibition of citrate synthase, which leads to the overall lowering of citrate levels. If glycolytic dysregulation occurs and produces low energy, due to the ineffectiveness in converting pyruvate into acetyl-CoA, alternative energy sources for fuel are used.
Why does acetyl-CoA inhibit pyruvate kinase?
Acetyl CoA might provide a rapid mechanism for (1) activating the gluconeogenic enzyme, pyruvate carboxylase; (2) preventing the recycling of phosphoenolpyruvate by inhibiting the glycolytic enzyme, pyruvate kinase; (3) blocking the initiation of glycolysis by inhibiting the activity of glucokinase.
What would be the effect of inhibiting pyruvate dehydrogenase kinase in normal cells?
Inhibition of pyruvate dehydrogenase kinase-1 by dicoumarol enhances the sensitivity of hepatocellular carcinoma cells to oxaliplatin via metabolic reprogramming.
What does pyruvate kinase do in glycolysis?
Pyruvate kinase is an enzyme that catalyzes the conversion of phosphoenolpyruvate and ADP to pyruvate and ATP in glycolysis and plays a role in regulating cell metabolism.
Is pyruvate dehydrogenase the same as pyruvate dehydrogenase kinase?
Pyruvate dehydrogenase (PDH) catalyzes the conversion of pyruvate to acetyl-coenzyme A, which enters into the Krebs cycle, providing adenosine triphosphate (ATP) to the cell. PDH activity is under the control of pyruvate dehydrogenase kinases (PDKs).
How do you inhibit pyruvate dehydrogenase?
Pyruvate dehydrogenase is regulated by end product inhibition by acetyl CoA (competitive with CoA) , NADH 2 (competitive NAD) and acetoin (competitive pyruvate); and through inactivation by phosphorylation catalysed by an intrinsic kinase utilising ATPMg++ and reactivation by a phosphatase.
What state of the PDH complex does insulin activate?
The mechanism of PDH phosphorylation–dephosphorylation is not dependent on the levels of cyclic AMP. Insulin promotes the activation of PDH phosphatase. The enzyme is stimulated by increased levels of intramitochondrial Ca2+ and inhibited by NADH. PDH activity in muscle tissue increases during intense exercise.
How does insulin work for diabetics?
Insulin helps blood sugar enter the body's cells so it can be used for energy. Insulin also signals the liver to store blood sugar for later use. Blood sugar enters cells, and levels in the bloodstream decrease, signaling insulin to decrease too.
Introduction
Hepatic steatosis is induced by a number of lipid metabolic abnormalities, including increased de novo lipogenesis, inhibited triacylglycerol (TG) release, enhanced fatty acid (FA) influx from adipose tissue, and reduced hepatic FA oxidation and ketogenesis ( 1 ).
Research Design and Methods
All experiments were approved by the Institutional Animal Care and Use Committee of Kyungpook National University. For the NAFLD mice model, 8-week-old male wild-type (WT) (C57BL/6J) and PDK2 knockout (KO) mice ( 13) were fed an HFD in which 20% of the calories were derived from carbohydrates and 60% from fat (D12492 pellets; Research Diets).
Results
PDK2 expression is increased in the livers of obese animals ( 9, 17 ), but its role in the development of hepatic metabolic diseases remains unclear. We examined PDC activity and the expression of PDK isoenzymes in the livers of WT mice fed an HFD. As shown in Fig.
Discussion
As the link between glycolysis and the TCA cycle and a precursor for gluconeogenesis and lipogenesis, pyruvate plays a critical role in both anabolic and catabolic metabolism depending upon the tissue and the physiological condition of the organism ( 22 ).
Article Information
Acknowledgments. The authors thank Dr. Youngmin Hong and Dr. Ji-Young Choi (Dong-il Shimadzu Corp. Technical Research Center, South Korea) for help with the analysis of hepatic metabolites using liquid chromatography–mass spectrometry.