Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Regulation of the activity of the pyruvate dehydrogenase complex in skeletal muscle plays an important role in fuel selection and glucose homeostasis. Activation of the complex promotes disposal of glucose, whereas inactivation conserves substrates for hepatic glucose production. Starvation and diabetes induce a stable increase in pyruvate dehydrogenase kinase activity in skeletal muscle mitochondria that promotes phosphorylation and inactivation of the complex. The present study shows that these metabolic conditions induce a large increase in the expression of PDK4, one of four pyruvate dehydrogenase kinase isoenzymes expressed in mammalian tissues, in the mitochondria of gastrocnemius muscle. Refeeding starved rats and insulin treatment of diabetic rats decreased pyruvate dehydrogenase kinase activity and also reversed the increase in PDK4 protein in gastrocnemius muscle mitochondria. Starvation and diabetes also increased the abundance of PDK4 mRNA in gastrocnemius muscle, and refeeding and insulin treatment again reversed the effects of starvation and diabetes. These findings suggest that an increase in amount of this enzyme contributes to hyperphosphorylation and inactivation of the pyruvate dehydrogenase complex in these metabolic conditions. It was further found that feeding rats WY-14,643, a selective agonist for the peroxisome proliferator-activated receptor-alpha (PPAR-alpha), also induced large increases in pyruvate dehydrogenase kinase activity, PDK4 protein, and PDK4 mRNA in gastrocnemius muscle. Since long-chain fatty acids activate PPAR-alpha endogenously, increased levels of these compounds in starvation and diabetes may signal increased expression of PDK4 in skeletal muscle.
 ...
PMID:Mechanism responsible for inactivation of skeletal muscle pyruvate dehydrogenase complex in starvation and diabetes. 1042 78

Pyruvate dehydrogenase kinase isoform 4 (PDK4) is upregulated by starvation in many tissues of the body during starvation. This causes inactivation of the pyruvate dehydrogenase complex which blocks pyruvate oxidation and conserves lactate and alanine for gluconeogenesis. Enhanced PDK4 expression may be caused by the increase in free fatty acids that occurs during starvation. Free fatty acids can activate peroxisome proliferator-activated receptor alpha (PPARalpha), and activation of PPARalpha can promote PDK4 expression. This model is supported by the findings reported here that WY-14,643, a synthetic PPARalpha activator, increases PDK4 expression in wild-type mice but not in PPARalpha-null mice. Starvation likewise increases the expression of PDK4 in tissues of wild-type mice but not in tissues of PPARalpha-null mice. These findings document the functional importance of PPARalpha for PDK4 expression during starvation and suggest an important role for elevated free fatty acids in the induction.
 ...
PMID:Adaptive increase in pyruvate dehydrogenase kinase 4 during starvation is mediated by peroxisome proliferator-activated receptor alpha. 1155 40

Pyruvate dehydrogenase kinase (PDK) catalyzes phosphorylation and inactivation of the pyruvate dehydrogenase complex (PDC). Two isoforms of this mitochondrial kinase (PDK2 and PDK4) are induced in a tissue-specific manner in response to starvation and diabetes. Inactivation of PDC by increased PDK activity promotes gluconeogenesis by conserving three-carbon substrates. This helps maintain glucose levels during starvation, but is detrimental in diabetes. Factors that regulate PDK2 and PDK4 expression were examined in Morris hepatoma 7800 C1 cells. The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist WY-14,643 and the glucocorticoid dexamethasone increased PDK4 mRNA levels. Neither compound affected the half-life of the PDK4 message, suggesting that both increase gene transcription. Fatty acids caused an increase in the PDK4 message comparable to that induced by WY-14,643. Insulin prevented and reversed the stimulatory effects of dexamethasone on PDK4 gene expression, but was less effective against the stimulatory effects of WY-14,643 and fatty acids. Insulin also decreased the abundance of the PDK2 message. The findings suggest that decreased levels of insulin and increased levels of fatty acids and glucocorticoids promote PDK4 gene expression in starvation and diabetes. The decreased level of insulin is likely responsible for the increase in PDK2 mRNA level in starvation and diabetes.
 ...
PMID:Regulation of pyruvate dehydrogenase kinase expression by peroxisome proliferator-activated receptor-alpha ligands, glucocorticoids, and insulin. 1181 33

Former studies in rats demonstrated that starvation or treatment with the hypolipidemic drug clofibrate causes a marked increase in the concentration of carnitine in the liver. The molecular mechanisms underlying these phenomena in rats, however, have been largely unknown. Since both, fasting and clofibrate treatment lead to an activation of peroxisome proliferator-activated receptor alpha (PPARalpha), the hypothesis has been raised that activation of this nuclear receptor could lead to an up-regulation of novel organic cation transporters (OCTN) which facilitate transport of carnitine and several other organic cations through membranes. Studies in rodents and pigs have indeed shown that treatment with PPARalpha agonists causes an up-regulation of OCTN2 in liver and other tissues such as muscle and small intestine. Additional experiments with PPARalpha-null and corresponding wild-type mice, which were either fasted or treated with the high-affinity PPARalpha agonist WY-14,643, revealed that transcriptional up-regulation of OCTN2 and OCTN3 is dependent on PPARalpha. An up-regulation of OCTN by PPARalpha activation could be regarded as a means to supply cells with sufficient carnitine required for transport of excessive amounts of fatty acids into the mitochondrion during fasting, and therefore plays an important role in the adaptive response of the metabolism to fasting. Due to the strong similarities in the gene response to PPARalpha agonists and the similar metabolic features and anatomic conditions between pigs and humans, it is likely that pharmacological PPARalpha agonists exert similar effects in humans.
 ...
PMID:The role of peroxisome proliferator-activated receptor alpha in transcriptional regulation of novel organic cation transporters. 1994 51

Cachexia is frequently accompanied by severe metabolic derangements, although the mechanisms responsible for this debilitating condition remain unclear. Pyruvate dehydrogenase kinase (PDK)4, a critical regulator of cellular energetic metabolism, was found elevated in experimental models of cancer, starvation, diabetes, and sepsis. Here we aimed to investigate the link between PDK4 and the changes in muscle size in cancer cachexia. High PDK4 and abnormal energetic metabolism were found in the skeletal muscle of colon-26 tumor hosts, as well as in mice fed a diet enriched in Pirinixic acid, previously shown to increase PDK4 levels. Viral-mediated PDK4 overexpression in myotube cultures was sufficient to promote myofiber shrinkage, consistent with enhanced protein catabolism and mitochondrial abnormalities. On the contrary, blockade of PDK4 was sufficient to restore myotube size in C2C12 cultures exposed to tumor media. Our data support, for the first time, a direct role for PDK4 in promoting cancer-associated muscle metabolic alterations and skeletal muscle atrophy.-Pin, F., Novinger, L. J., Huot, J. R., Harris, R. A., Couch, M. E., O'Connell, T. M., Bonetto, A. PDK4 drives metabolic alterations and muscle atrophy in cancer cachexia.
 ...
PMID:PDK4 drives metabolic alterations and muscle atrophy in cancer cachexia. 3089 18