Mechanisms underlying regulation of the expression and activities of the mammalian pyruvate dehydrogenase kinases.
The mechanisms that control mammalian pyruvate dehydrogenase complex (PDC) activity include its phosphorylation (inactivation) by a family of pyruvate dehydrogenase kinases (PDKs 1 - 4). Here we review new developments in the regulation of the activities and expression of the PDKs, in particular PDK2 and PDK4, in relation to glucose and lipid homeostasis. This review describes recent advances relating to the acute and long-term modes of regulation of the PDKs, with particular emphasis on the regulatory roles of nuclear receptors including peroxisome proliferator-activated receptor (PPAR) alpha and Liver X receptor (LXR), PPAR gamma coactivator alpha (PGC-1alpha) and insulin, and the impact of changes in PDK activity and expression in glucose and lipid homeostasis. Since PDK4 may assist in lipid clearance when there is an imbalance between lipid delivery and oxidation, it may represent an attractive target for interventions aimed at rectifying abnormal lipid as well as glucose homeostasis in disease states.
Sugden
Mary C
MC
Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, Bart's and the London, Queen Mary's School of Medicine and Dentistry, London, UK. m.c.sugden@qmul.ac.uk
Holness
Mark J
MJ
D000818:Animals; D005227:Fatty Acids / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D005227:Fatty Acids; D006360:Heat-Shock Proteins; D007328:Insulin; D007527:Isoenzymes; C000631430:PDK2 protein, human; C000631432:PDK4 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D014157:Transcription Factors; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; D017346:Protein Serine-Threonine Kinases