Document Detail

Fuel-sensing mechanisms integrating lipid and carbohydrate utilization.
MedLine Citation:
PMID:  11356166     Owner:  NLM     Status:  MEDLINE    
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.
M C Sugden; K Bulmer; M J Holness
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biochemical Society transactions     Volume:  29     ISSN:  0300-5127     ISO Abbreviation:  Biochem. Soc. Trans.     Publication Date:  2001 May 
Date Detail:
Created Date:  2001-05-17     Completed Date:  2001-09-06     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  7506897     Medline TA:  Biochem Soc Trans     Country:  England    
Other Details:
Languages:  eng     Pagination:  272-8     Citation Subset:  IM    
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.
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MeSH Terms
Carbohydrate Metabolism*
Energy Metabolism*
Fatty Acids / metabolism
Gene Expression Regulation, Enzymologic
Glucose / metabolism
Insulin / deficiency,  metabolism
Isoenzymes / metabolism
Kidney / enzymology
Lactic Acid / metabolism
Lipid Metabolism*
Liver / enzymology
Muscles / enzymology,  metabolism
Oxidative Stress
Protein Kinases / metabolism
Receptors, Cytoplasmic and Nuclear / metabolism
Transcription Factors / metabolism
Reg. No./Substance:
0/Fatty Acids; 0/Isoenzymes; 0/Receptors, Cytoplasmic and Nuclear; 0/Transcription Factors; 11061-68-0/Insulin; 50-21-5/Lactic Acid; 50-99-7/Glucose; EC 2.7.-/Protein Kinases; EC 2.7.1.-/pyruvate dehydrogenase kinase 4

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