Diabetes Metab J.  2012 Oct;36(5):328-335. 10.4093/dmj.2012.36.5.328.

Transcriptional Regulation of Pyruvate Dehydrogenase Kinase

• Jeong JY
• Jeoung NH
• Park KG
• Lee IK

• KMID: 2174390
• DOI: http://doi.org/10.4093/dmj.2012.36.5.328

Abstract

The pyruvate dehydrogenase complex (PDC) activity is crucial to maintains blood glucose and ATP levels, which largely depends on the phosphorylation status by pyruvate dehydrogenase kinase (PDK) isoenzymes. Although it has been reported that PDC is phosphorylated and inactivated by PDK2 and PDK4 in metabolically active tissues including liver, skeletal muscle, heart, and kidney during starvation and diabetes, the precise mechanisms by which expression of PDK2 and PDK4 are transcriptionally regulated still remains unclear. Insulin represses the expression of PDK2 and PDK4 via phosphorylation of FOXO through PI3K/Akt signaling pathway. Several nuclear hormone receptors activated due to fasting or increased fat supply, including peroxisome proliferator-activated receptors, glucocorticoid receptors, estrogen-related receptors, and thyroid hormone receptors, also participate in the up-regulation of PDK2 and PDK4; however, the endogenous ligands that bind those nuclear receptors have not been identified. It has been recently suggested that growth hormone, adiponectin, epinephrine, and rosiglitazone also control the expression of PDK4 in tissue-specific manners. In this review, we discuss several factors involved in the expressional regulation of PDK2 and PDK4, and introduce current studies aimed at providing a better understanding of the molecular mechanisms that underlie the development of metabolic diseases such as diabetes.

Keyword

Insulin resistance; Pyruvate dehydrogenase kinase; Receptors, cytoplasmic and nuclear; Transcriptional regulation

MeSH Terms

Adenosine Triphosphate
Adiponectin
Blood Glucose
Epinephrine
Fasting
Growth Hormone
Heart
Insulin
Insulin Resistance
Isoenzymes
Kidney
Ligands
Liver
Metabolic Diseases
Muscle, Skeletal
Oxidoreductases
Peroxisome Proliferator-Activated Receptors
Phosphorylation
Phosphotransferases
Protein-Serine-Threonine Kinases
Pyruvate Dehydrogenase Complex
Pyruvic Acid
Receptors, Cytoplasmic and Nuclear
Receptors, Glucocorticoid
Receptors, Thyroid Hormone
Starvation
Thiazolidinediones
Up-Regulation
Adenosine Triphosphate
Adiponectin
Blood Glucose
Epinephrine
Growth Hormone
Insulin
Isoenzymes
Ligands
Oxidoreductases
Peroxisome Proliferator-Activated Receptors
Phosphotransferases
Protein-Serine-Threonine Kinases
Pyruvate Dehydrogenase Complex
Pyruvic Acid
Receptors, Cytoplasmic and Nuclear
Receptors, Glucocorticoid
Receptors, Thyroid Hormone
Thiazolidinediones

Figure

• 

  Fig. 1 Regulation of pyruvate dehydrogenase kinases (PDKs) by allosteric effectors. Among the products and substrates of pyruvate dehydrogenase complex (PDC), pyruvate, CoA, and nicotinamide adenine dinucleotide (NAD+) suppress PDK activity, while acetyl coenzyme A (acetyl-CoA) and NADH activate PDKs. ADP produced by the kinase reaction also inhibits PDK activity. TCA cycle, tricarboxylic acid cycle.

• 

  Fig. 2 Schematic representation of transcriptional control of pyruvate dehydrogenase kinase 4 (PDK4) expression. Activation of Akt/PKB signaling by insulin phosphorylates forkhead box protein O (FOXO) and suppresses PDK4 expression. Several nuclear receptors, including estrogen-related receptor (ERR), peroxisome proliferator-activated receptor (PPAR), glucocorticoid receptor (GR), and thyroid hormone receptor (TR), participate in the transcriptional regulation of PDK4 and coordinate with coactivators, including peroxisome proliferator-activated receptor gamma coactivator 1-α (PCG-1α) and CCAAT/enhancer binding protein β (C/EBPβ).

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