Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs.
- M. Sugden, M. Holness
- Biology, Computer ScienceAmerican Journal of Physiology. Endocrinology and…
- 1 May 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.
Regulation of pyruvate dehydrogenase complex activity by reversible phosphorylation.
The concept that thePDKs act as tissue homoeostats is developed and it is suggested that long-term modulation of expression of individual PDKs, particularly PDK4, is an essential component of allostasis to maintain Homoeostasis.
Mechanisms underlying regulation of the expression and activities of the mammalian pyruvate dehydrogenase kinases
Recent advances relating to the acute and long-term modes of regulation of the PDKs are described, with particular emphasis on the regulatory roles of nuclear receptors, PPAR γ coactivator α (PGC-1α) and insulin, and the impact of changes in PDK activity and expression in glucose and lipid homeostasis.
PPAR control: it's SIRTainly as easy as PGC.
It is evaluated the possibility that SIRT1 lies at the heart of a regulatory loop involving PPARalpha, PGC-1alpha, PPARA, PPARGC1A, and lipin-1 that ultimately controls the metabolic response to varying nutrient and physiological signals via a common mechanism mediated by post-translation modifications (deacetylation) of both PPAR alpha and P GC-1s.
Fibre-type specific modification of the activity and regulation of skeletal muscle pyruvate dehydrogenase kinase (PDK) by prolonged starvation and refeeding is associated with targeted regulation of…
It is concluded that targeted regulation of PDK4 isoenzyme expression in skeletal muscle in response to starvation and refeeding underlies the modulation of the regulatory characteristics ofPDK in vivo.
Gender-specific programming of insulin secretion and action.
It is demonstrated that exposure to protein restriction during early life alone leads to relative insulin resistance and hyperinsulinaemia in adulthood, but this relationship is gender specific, observed only in males, and glucose tolerance is maintained.
Fuel-sensing mechanisms integrating lipid and carbohydrate utilization.
- M. Sugden, K. Bulmer, M. Holness
- Biology, Environmental ScienceBiochemical Society Transactions
- 1 May 2001
The hypothesis that PDK4 is a "lipid status"-responsive PDK isoform facilitating FA oxidation and signalling through citrate formation is developed, and substrate interactions at the level of gene transcription extend glucose-FA interactions to the longer term.
Sirtuin 3 regulates mouse pancreatic beta cell function and is suppressed in pancreatic islets isolated from human type 2 diabetic patients
Decreased beta cell SIRT3 levels could be a key step in the onset of beta cell dysfunction, occurring via abnormal elevation of ROS levels and amplification ofbeta cell IL1β synthesis.
Targeted upregulation of pyruvate dehydrogenase kinase (PDK)-4 in slow-twitch skeletal muscle underlies the stable modification of the regulatory characteristics of PDK induced by high-fat feeding.
High-fat feeding leads to selective upregulation of PDK4 expression in slow-twitch muscle in response to high-Fat feeding in vivo, which is associated with a pronounced loss of sensitivity ofPDK activity to acute inhibition by pyruvate.
Endogenous Epoxygenases Are Modulators of Monocyte/Macrophage Activity
Epoxygenase activity represents an important endogenous pathway which limits monocyte activation and endogenous epoxygenases are immuno-modulators regulating monocyte/macrophage activation depending on the underlying activation state.