Fuel-sensing mechanisms integrating lipid and carbohydrate utilization.
Fuel metabolism is highly regulated to ensure adequate energy for cellular function. The contribution of the major metabolic fuels--glucose, lactate and fatty acids (FAs)--often reflects their circulating levels. In addition, regulatory cross-talk and fuel-induced hormone secretion ensures appropriate and co-ordinate fuel utilization. Because its activity can either determine or reflect fuel preference (carbohydrate versus fat), the pyruvate dehydrogenase complex (PDC) occupies a pivotal position in fuel cross-talk. Active PDC permits glucose oxidation and allows the formation of mitochondrially derived intermediates (e.g. malonyl-CoA and citrate) that reflect fuel abundance. FA oxidation suppresses PDC activity. PDC inactivation by phosphorylation is catalysed by pyruvate dehydrogenase kinases (PDKs) 1-4, which are regulated differentially by metabolite effectors. Most tissues contain at least two and often three of the PDK isoforms. We develop the hypothesis that PDK4 is a "lipid status"-responsive PDK isoform facilitating FA oxidation and signalling through citrate formation. Substrate interactions at the level of gene transcription extend glucose-FA interactions to the longer term. We discuss potential targets for substrate-mediated transcriptional regulation in relation to selective PDK isoform expression and the influence of altered PDK isoform expression in fuel sensing, selection and utilization.
Sugden
M C
MC
Department of Diabetes and Metabolic Medicine, St Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary, University of London, London E1 4NS, U.K. m.c.sugden@qmw.ac.uk
Bulmer
K
K
Holness
M J
MJ
D050260:Carbohydrate Metabolism; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000172:deficiency / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007668:Kidney / Q000201:enzymology; D019344:Lactic Acid / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000201:enzymology; D009132:Muscles / Q000201:enzymology / Q000378:metabolism; D018384:Oxidative Stress; D011494:Protein Kinases / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013217:Starvation; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
D005227:Fatty Acids; D007328:Insulin; D007527:Isoenzymes; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D019344:Lactic Acid; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; D005947:Glucose