Diverging regulation of pyruvate dehydrogenase kinase isoform gene expression in cultured human muscle cells

  title={Diverging regulation of pyruvate dehydrogenase kinase isoform gene expression in cultured human muscle cells},
  author={Emily L. Abbot and James G. Mccormack and Christine Reynet and David G. Hassall and Kevin W. Buchan and Stephen J. Yeaman},
  journal={The FEBS Journal},
The pyruvate dehydrogenase complex occupies a central and strategic position in muscle intermediary metabolism and is primarily regulated by phosphorylation/dephosphorylation. The identification of multiple isoforms of pyruvate dehydrogenase kinase (PDK1–4) and pyruvate dehydrogenase phosphatase (PDP1–2) has raised intriguing new possibilities for chronic pyruvate dehydrogenase complex control. Experiments to date suggest that PDK4 is the major isoenzyme responsible for changes in pyruvate… 

Pyruvate dehydrogenase kinase 4 expression is synergistically induced by AMP-activated protein kinase and fatty acids

It is shown that AMP-activated protein kinase activation by hypoxia and AICAR treatment combined with fatty acid administration synergistically induce PDK4 expression, and that this synergistic induction of PDK 4 decreases cellular glucose oxidation.

Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer

Activation of PDC by synthetic PDK inhibitors binding at the pyruvate or lipoyl binding sites decreased damage during heart ischemia and lowered blood glucose in insulin-resistant animals and triggers apoptosis in cancer cells that selectively convert glucose to lactate.

Role of Pyruvate Dehydrogenase Kinase 4 in Regulation of Blood Glucose Levels

PDK4 knockout mice have lower fasting blood glucose levels than wild type mice, proving that up regulation of PDK4 is important for normal glucose homeostasis and suggesting PDK 4 inhibitors might prove useful in the treatment of type 2 diabetes.

Regulation of PDK mRNA by high fatty acid and glucose in pancreatic islets.

Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation.

A novel mechanism by which ECM attachment, growth factors, and oncogenes modulate the metabolic fate of glucose by controlling PDK4 expression and PDH flux to influence proliferation is identified.

Regulation of Muscle Pyruvate Dehydrogenase Complex in Insulin Resistance: Effects of Exercise and Dichloroacetate

Life style intervention such as exercise, which is the most potent physiological activator of muscle PDC, along with pharmacological intervention can prove to be viable strategies for treating muscle insulin resistance in obesity and T2D as they can potentially restore whole body glucose disposal.

Novel molecular mechanisms involved in hormonal regulation of lactate production in Sertoli cells.

The aim of the study was to analyze molecular mechanisms involved in FSH and basic fibroblast growth factor (bFGF) regulation of lactate production in rat Sertoli cells, and showed that bFGF increases phosphorylated PDC levels and that FSH-stimulated lactateProduction is partially inhibited in the presence of a PDK inhibitor.



Starvation increases the amount of pyruvate dehydrogenase kinase in several mammalian tissues.

The findings of this study indicate that increased expression of PDK isoenzymes is an important mechanism for bringing about inactivation of the pyruvate dehydrogenase complex during starvation in many but not all tissues of the body.

Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs.

  • M. SugdenM. Holness
  • Biology, Computer Science
    American journal of physiology. Endocrinology and metabolism
  • 2003
Recent significant advances in knowledge of the mechanisms regulating PDC are summarized, with emphasis on the PDKs, in particular PDK4, whose expression is linked with sustained changes in tissue lipid handling and which may represent an attractive target for pharmacological interventions aimed at modulating whole body glucose, lipid, and lactate homeostasis in disease states.

Mechanism responsible for inactivation of skeletal muscle pyruvate dehydrogenase complex in starvation and diabetes.

It was found that feeding rats WY-14,643, a selective agonist for the peroxisome proliferator-activated receptor-alpha (PPAR-alpha), also induced large increases in pyruvate dehydrogenase kinase activity, PDK4 protein, andPDK4 mRNA in gastrocnemius muscle.

Adaptive increase in pyruvate dehydrogenase kinase 4 during starvation is mediated by peroxisome proliferator-activated receptor alpha.

The functional importance of PPARalpha for PDK4 expression during starvation is documented and an important role for elevated free fatty acids in the induction is suggested.

Starvation and diabetes reduce the amount of pyruvate dehydrogenase phosphatase in rat heart and kidney.

Findings indicate that opposite changes in expression of specific PDK and PDP isoenzymes contribute to hyperphosphorylation and therefore inactivation of the PDC in heart and kidney during starvation and diabetes.

Insulin downregulates pyruvate dehydrogenase kinase (PDK) mRNA: potential mechanism contributing to increased lipid oxidation in insulin-resistant subjects.

The data indicate that insufficient downregulation of PDK mRNA in insulin-resistant individuals could be a cause of increased PDK expression leading to impaired glucose oxidation followed by increased FA oxidation.

Starvation and diabetes increase the amount of pyruvate dehydrogenase kinase isoenzyme 4 in rat heart.

Control of the amount of PDK4 is important in long-term regulation of the activity of the pyruvate dehydrogenase complex in rat heart, indicating that the effects of starvation and diabetes on heart PDK activity are likely to be limited.

Protein kinase B-alpha inhibits human pyruvate dehydrogenase kinase-4 gene induction by dexamethasone through inactivation of FOXO transcription factors.

Mechanisms that regulate PDK4 gene expression, previously established to be increased by glucocorticoids and decreased by insulin, were studied and transfection studies with E1A suggest that interactions between p300/CBP and GR as well as FOXO factors are important for glucOCorticoid-stimulated hPDK4 expression.

Diversity of the Pyruvate Dehydrogenase Kinase Gene Family in Humans *

The deduced amino acid sequences of three isoenzymic forms of PDK found in humans suggest that PDK2 is a major isoenzyme responsible for regulation of pyruvate dehydrogenase in human tissues, and PDK3 appears to have the highest specific activity among the three isenzymes tested as recombinant proteins.

Insulin action in cultured human myoblasts: contribution of different signalling pathways to regulation of glycogen synthesis.

Findings suggest that protein kinase B is responsible for the inactivation of GSK-3, but that an additional rapamycin-sensitive mechanism may contribute to the activation of GS and stimulation of glycogen synthesis.