scholarly journals Coenzyme A–mediated degradation of pyruvate dehydrogenase kinase 4 promotes cardiac metabolic flexibility after high-fat feeding in mice

2018 ◽  
Vol 293 (18) ◽  
pp. 6915-6924 ◽  
Author(s):  
Christopher Schafer ◽  
Zachary T. Young ◽  
Catherine A. Makarewich ◽  
Abdallah Elnwasany ◽  
Caroline Kinter ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Coenzyme A ◽  
Pyruvate Dehydrogenase Kinase ◽  
Metabolic Flexibility ◽  
High Fat ◽  
Pyruvate Dehydrogenase Kinase 4 ◽  
Fat Feeding

Overexpression of pyruvate dehydrogenase kinase 4 in heart perturbs metabolism and exacerbates calcineurin-induced cardiomyopathy

2008 ◽  
Vol 294 (2) ◽  
pp. H936-H943 ◽  
Author(s):  
Guixiang Zhao ◽  
Nam Ho Jeoung ◽  
Shawn C. Burgess ◽  
Kimberly A. Rosaaen-Stowe ◽  
Takeshi Inagaki ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Pyruvate Dehydrogenase ◽  
Marked Decrease ◽  
Active Form ◽  
Pyruvate Dehydrogenase Kinase ◽  
Metabolic Flexibility ◽  
Energy Demands ◽  
Pyruvate Dehydrogenase Kinase 4 ◽  
Fatty Acid Catabolism

The heart adapts to changes in nutritional status and energy demands by adjusting its relative metabolism of carbohydrates and fatty acids. Loss of this metabolic flexibility such as occurs in diabetes mellitus is associated with cardiovascular disease and heart failure. To study the long-term consequences of impaired metabolic flexibility, we have generated mice that overexpress pyruvate dehydrogenase kinase (PDK)4 selectively in the heart. Hearts from PDK4 transgenic mice have a marked decrease in glucose oxidation and a corresponding increase in fatty acid catabolism. Although no overt cardiomyopathy was observed in the PDK4 transgenic mice, introduction of the PDK4 transgene into mice expressing a constitutively active form of the phosphatase calcineurin, which causes cardiac hypertrophy, caused cardiomyocyte fibrosis and a striking increase in mortality. These results demonstrate that cardiac-specific overexpression of PDK4 is sufficient to cause a loss of metabolic flexibility that exacerbates cardiomyopathy caused by the calcineurin stress-activated pathway.

scholarly journals Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and improves glucose tolerance in diet-induced obese mice

2008 ◽  
Vol 295 (1) ◽  
pp. E46-E54 ◽  
Author(s):  
Nam Ho Jeoung ◽  
Robert A. Harris
Keyword(s):  
Skeletal Muscle ◽  
Blood Glucose ◽  
Glucose Tolerance ◽  
Pyruvate Dehydrogenase ◽  
High Fat Diet ◽  
Pyruvate Dehydrogenase Kinase ◽  
Wild Type ◽  
High Fat ◽  
Pyruvate Dehydrogenase Kinase 4 ◽  
Liver And Kidney

The effect of pyruvate dehydrogenase kinase-4 (PDK4) deficiency on glucose homeostasis was studied in mice fed a high-fat diet. Expression of PDK4 was greatly increased in skeletal muscle and diaphragm but not liver and kidney of wild-type mice fed the high-fat diet. Wild-type and PDK4−/− mice consumed similar amounts of the diet and became equally obese. Insulin resistance developed in both groups. Nevertheless, fasting blood glucose levels were lower, glucose tolerance was slightly improved, and insulin sensitivity was slightly greater in the PDK4−/− mice compared with wild-type mice. When the mice were killed in the fed state, the actual activity of the pyruvate dehydrogenase complex (PDC) was higher in the skeletal muscle and diaphragm but not in the liver and kidney of PDK4−/− mice compared with wild-type mice. When the mice were killed after overnight fasting, the actual PDC activity was higher only in the kidney of PDK4−/− mice compared with wild-type mice. The concentrations of gluconeogenic substrates were lower in the blood of PDK4−/− mice compared with wild-type mice, consistent with reduced formation in peripheral tissues. Diaphragms isolated from PDK4−/− mice oxidized glucose faster and fatty acids slower than diaphragms from wild-type mice. Fatty acid oxidation inhibited glucose oxidation by diaphragms from wild-type but not PDK4−/− mice. NEFA, ketone bodies, and branched-chain amino acids were elevated more in PDK4−/− mice, consistent with slower rates of oxidation. These findings show that PDK4 deficiency lowers blood glucose and slightly improves glucose tolerance and insulin sensitivity in mice with diet-induced obesity.

scholarly journals Investigation of potential mechanisms regulating protein expression of hepatic pyruvate dehydrogenase kinase isoforms 2 and 4 by fatty acids and thyroid hormone

2003 ◽  
Vol 369 (3) ◽  
pp. 687-695 ◽  
Author(s):  
Mark J. HOLNESS ◽  
Karen BULMER ◽  
Nicholas D. SMITH ◽  
Mary C. SUGDEN
Keyword(s):  
Thyroid Hormone ◽  
Protein Expression ◽  
Pyruvate Dehydrogenase ◽  
Hormone Receptors ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Dehydrogenase Kinase ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Cpt I ◽  
Fat Feeding

Liver contains two pyruvate dehydrogenase kinases (PDKs), namely PDK2 and PDK4, which regulate glucose oxidation through inhibitory phosphorylation of the pyruvate dehydrogenase complex (PDC). Starvation increases hepatic PDK2 and PDK4 protein expression, the latter occurring, in part, via a mechanism involving peroxisome proliferator-activated receptor-α (PPARα). High-fat feeding and hyperthyroidism, which increase circulating lipid supply, enhance hepatic PDK2 protein expression, but these increases are insufficient to account for observed increases in hepatic PDK activity. Enhanced expression of PDK4, but not PDK2, occurs in part via a mechanism involving PPAR-α. Heterodimerization partners for retinoid X receptors (RXRs) include PPARα and thyroid-hormone receptors (TRs). We therefore investigated the responses of hepatic PDK protein expression to high-fat feeding and hyperthyroidism in relation to hepatic lipid delivery and disposal. High-fat feeding increased hepatic PDK2, but not PDK4, protein expression whereas hyperthyroidism increased both hepatic PDK2 and PDK4 protein expression. Both manipulations decreased the sensitivity of hepatic carnitine palmitoyltransferase I (CPT I) to suppression by malonyl-CoA, but only hyperthyrodism elevated plasma fatty acid and ketone-body concentrations and CPT I maximal activity. Administration of the selective PPAR-α activator WY14,643 significantly increased PDK4 protein to a similar extent in both control and high-fat-fed rats, but WY14,643 treatment and hyperthyroidism did not have additive effects on hepatic PDK4 protein expression. PPARα activation did not influence hepatic PDK2 protein expression in euthyroid rats, suggesting that up-regulation of PDK2 by hyperthyroidism does not involve PPARα, but attenuated the effect of hyperthyroidism to increase hepatic PDK2 expression. The results indicate that hepatic PDK4 up-regulation can be achieved by heterodimerization of either PPARα or TR with the RXR receptor and that effects of PPARα activation on hepatic PDK2 and PDK4 expression favour a switch towards preferential expression of PDK4.

scholarly journals High-Fat/Low-Carbohydrate Diet Reduces Insulin-Stimulated Carbohydrate Oxidation but Stimulates Nonoxidative Glucose Disposal in Humans: An Important Role for Skeletal Muscle Pyruvate Dehydrogenase Kinase 4

2007 ◽  
Vol 92 (1) ◽  
pp. 284-292 ◽  
Author(s):  
K. Chokkalingam ◽  
K. Jewell ◽  
L. Norton ◽  
J. Littlewood ◽  
L. J. C. van Loon ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Glycogen Storage ◽  
Pyruvate Dehydrogenase Kinase ◽  
Whole Body ◽  
Glucose Disposal ◽  
High Fat ◽  
Complex Activity ◽  
Pyruvate Dehydrogenase Kinase 4 ◽  
Low Carbohydrate

Abstract Aim: The aim of this report was to study the effect of high-fat (HF)/low-carbohydrate (CHO) diet on regulation of substrate metabolism in humans. Methods: Ten healthy men consumed either a HF (75% energy as fat) or control (35%) diet for 6 d in random order. On d 7, blood glucose disappearance rate (Rd) was determined before and during a hyperinsulinemic euglycemic clamp. Substrate oxidation was determined by indirect calorimetry. Muscle biopsies were obtained prediet, postdiet, and postclamps. Results: Rd was similar under basal conditions but slightly elevated (∼10%, P < 0.05) during the last 30 min of the clamp after the HF diet. HF diet reduced CHO oxidation under basal (by ∼40%, P < 0.05) and clamp conditions (by ∼20%, P < 0.05), increased insulin-mediated whole-body nonoxidative glucose disposal (by 30%, P < 0.05) and muscle glycogen storage (by ∼25%, P < 0.05). Muscle pyruvate dehydrogenase complex activity was blunted under basal and clamp conditions after HF compared with control (P < 0.05) and was accompanied by an approximately 2-fold increase (P < 0.05) in pyruvate dehydrogenase kinase 4 (PDK4) mRNA and protein expression. Conclusion: Short-term HF/low-CHO dietary intake did not induce whole-body insulin resistance, but caused a shift in im glucose metabolism from oxidation to glycogen storage. Insulin-stimulated CHO oxidation and muscle pyruvate dehydrogenase complex activity were blunted after the HF diet. Up-regulation of muscle PDK4 expression was an early molecular adaptation to these changes, and we showed for the first time in healthy humans, unlike insulin-resistant individuals, that insulin can suppress PDK4 but not PDK2 gene expression in skeletal muscle.

Long-term regulation of pyruvate dehydrogenase kinase by high-fat feeding

FEBS Letters ◽  
1993 ◽  
Vol 336 (3) ◽  
pp. 501-505 ◽  
Author(s):  
Karen A. Orfali ◽  
Lee G.D. Fryer ◽  
Mark J. Holness ◽  
Mary C. Sugden
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Kinase ◽  
High Fat ◽  
Fat Feeding

scholarly journals Anti-Warburg Effect of Melatonin: A Proposed Mechanism to Explain its Inhibition of Multiple Diseases

2021 ◽  
Vol 22 (2) ◽  
pp. 764
Author(s):  
Russel J. Reiter ◽  
Ramaswamy Sharma ◽  
Sergio Rosales-Corral
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Warburg Effect ◽  
Coenzyme A ◽  
Aerobic Glycolysis ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Dehydrogenase Kinase ◽  
Metabolic Phenotype ◽  
Common Denominator ◽  
Acetyl Coenzyme A ◽  
Acetyl Coenzyme

Glucose is an essential nutrient for every cell but its metabolic fate depends on cellular phenotype. Normally, the product of cytosolic glycolysis, pyruvate, is transported into mitochondria and irreversibly converted to acetyl coenzyme A by pyruvate dehydrogenase complex (PDC). In some pathological cells, however, pyruvate transport into the mitochondria is blocked due to the inhibition of PDC by pyruvate dehydrogenase kinase. This altered metabolism is referred to as aerobic glycolysis (Warburg effect) and is common in solid tumors and in other pathological cells. Switching from mitochondrial oxidative phosphorylation to aerobic glycolysis provides diseased cells with advantages because of the rapid production of ATP and the activation of pentose phosphate pathway (PPP) which provides nucleotides required for elevated cellular metabolism. Molecules, called glycolytics, inhibit aerobic glycolysis and convert cells to a healthier phenotype. Glycolytics often function by inhibiting hypoxia-inducible factor-1α leading to PDC disinhibition allowing for intramitochondrial conversion of pyruvate into acetyl coenzyme A. Melatonin is a glycolytic which converts diseased cells to the healthier phenotype. Herein we propose that melatonin’s function as a glycolytic explains its actions in inhibiting a variety of diseases. Thus, the common denominator is melatonin’s action in switching the metabolic phenotype of cells.

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