Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.2 (PDK1)
2,238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The review examines the mechanisms regulating the activities of the two key enzymes determining rates of glucose and fatty acid oxidation, i.e., the pyruvate dehydrogenase (PDH) complex and the carnitine palmitoyltransferase (CPT) system. The review also evaluates the regulatory importance of gene expression in the control of tissue fuel selection within the context of substrate competition between glucose and fatty acids. It identifies a strong indirect input of nutrient-gene interactions in the control of pyruvate oxidation through the regulated provision of pyruvate as a substrate for PDH and as an inhibitor of PDH kinase. Nutrient-gene interactions are also identified in relation to the regulation of CPT I activity by malonyl-CoA (inhibitor) and by the provision of long-chain acyl-CoA (substrate/activator), the latter via the hydrolysis of plasma or tissue triacylglycerol (by lipoprotein lipase and hormone-sensitive lipase, respectively). We discuss how such regulation is reinforced by long-term modulation of PDH kinase-specific activity and CPT I maximal activity. We also explore the role of mechanisms operating at the levels of the PDH complex and the CPT system that act to promote and accelerate a switch in fuel utilization once a committed change in nutrient supply has been established. In particular, we discuss the regulatory influences exerted by altered sensitivities of PDH kinase to inhibition by pyruvate and CPT I to inhibition by malonyl-CoA, respectively.
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PMID:Interactive regulation of the pyruvate dehydrogenase complex and the carnitine palmitoyltransferase system. 829 90

Concurrent with the spread of the western lifestyle, the prevalence of all types of diabetes is on the rise in the world's population. The number of diabetics is increasing by 4-5% per year with an estimated 40-45% of individual's over the age of 65 years having either type II diabetes or impaired glucose tolerance. Since the signs of diabetes are not immediately obvious, diagnosis can be preceded by an extended period of impaired glucose tolerance resulting in the prevalence of beta-cell dysfunction and macrovascular complications. In addition to increased medical vigilance, diabetes is being combatted through aggressive treatment directed at lowering circulating blood glucose and inhibiting postprandial hyperglycemic spikes. Current strategies to treat diabetes include reducing insulin resistance using glitazones, supplementing insulin supplies with exogenous insulin, increasing endogenous insulin production with sulfonylureas and meglitinides, reducing hepatic glucose production through biguanides, and limiting postprandial glucose absorption with alpha-glucosidase inhibitors. In all of these areas, new generations of small molecules are being investigated which exhibit improved efficacy and safety profiles. Promising biological targets are also emerging such as (1) insulin sensitizers including protein tyrosine phosphatase-1B (PTP-1B) and glycogen synthase kinase 3 (GSK3), (2) inhibitors of gluconeogenesis like pyruvate dehydrogenase kinase (PDH) inhibitors, (3) lipolysis inhibitors, (4) fat oxidation including carnitine palmitoyltransferase (CPT) I and II inhibitors, and (5) energy expenditure by means of beta 3-adrenoceptor agonists. Also important are alternative routes of glucose disposal such as Na+-glucose cotransporter (SGLT) inhibitors, combination therapies, and the treatment of diabetic complications (eg. retinopathy, nephropathy, and neuropathy). With may new opportunities for drug discovery, the prospects are excellent for development of innovative therapies to effectively manage diabetes and prevent its long term complications. This review highlights recent (1997-2000) advances in diabetes therapy and research with an emphasis on small molecule drug design (275 references).
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PMID:Current therapies and emerging targets for the treatment of diabetes. 1128 51

We tested the hypothesis that hypoxia decreases PPARalpha-regulated gene expression in heart muscle in vivo. In two rat models of systemic hypoxia (cobalt chloride treatment and iso-volemic hemodilution), transcript levels of PPARalpha and PPARalpha-regulated genes (pyruvate dehydrogenase kinase 4 (PDK4), muscle carnitine palmitoyltransferase-I (mCPT-I), and malonyl-CoA decarboxylase (MCD)) were measured using real-time quantitative RT-PCR. Data were normalized to the housekeeping gene beta-actin. Atrial natriuretic factor (ANF) and pyruvate dehydrogenase kinase 2 (PDK2), which are not regulated by PPARalpha, served as controls. CoCl(2) treatment decreased PPARalpha, PDK4, mCPT-I, and MCD mRNA levels. Iso-volemic anemia also caused a significant decrease in PPARalpha, PDK4, and MCD mRNA levels. Transcript levels of mCPT-I showed a slight, but not significant decrease (P = 0.08). Gene expression of beta-actin, ANF, and PDK2 did not change with either CoCl(2) treatment nor with anemia. Myocardial PPARalpha-regulated gene expression is decreased in two models of hypoxia in vivo. These results suggest a transcriptional mechanism for decreased fatty oxidation and increased reliance of the heart for glucose during hypoxia.
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PMID:Hypoxia in vivo decreases peroxisome proliferator-activated receptor alpha-regulated gene expression in rat heart. 1154 45

The mitochondrial pyruvate dehydrogenase complex (PDC) catalyses the oxidative decarboxylation of pyruvate, and links glycolysis to the tricarboxylic acid cycle and ATP production. Adequate flux through PDC is important in tissues with a high ATP requirement, in lipogenic tissues (since it provides cytosolic acetyl-CoA for fatty acid (FA) synthesis), and in generating cytosolic malonyl-CoA, a potent inhibitor of carnitine palmitoyltransferase (CPT I). Conversely, suppression of PDC activity is crucial for glucose conservation when glucose is scarce. This review describes recent advances relating to the control of mammalian PDC activity by phosphorylation (inactivation) and dephosphorylation (activation, reactivation), in particular regulation of PDC by pyruvate dehydrogenase kinase (PDK) which phosphorylates and inactivates PDC. PDK activity is that of a family of four proteins (PDK1-4). PDK2 and PDK4 appear to be expressed in most major tissues and organs of the body, PDK1 appears to be limited to the heart and pancreatic islets, and PDK3 is limited to the kidney, brain and testis. PDK4 is selectively upregulated in the longer term in most tissues and organs in response to starvation and hormonal imbalances such as insulin resistance, diabetes mellitus and hyperthyroidism. Parallel increases in PDK2 and PDK4 expression appear to be restricted to gluconceogenesic tissues, liver and kidney, which take up as well as generate pyruvate. Factors that regulate PDK4 expression include FA oxidation and adequate insulin action. PDK4 is also either a direct or indirect target of peroxisome proliferator-activated receptor (PPAR) alpha. PPAR alpha deficiency in liver and kidney restricts starvation-induced upregulation of PDK4; however, the role of PPAR alpha in heart and skeletal muscle appears to be more complex. These observations may have important implications for the pharmacological modulation of PDK activity (e.g. use of PPAR alpha activators) for the control of whole-body glucose, lipid and lactate homeostasis in disease states and suggest that therapeutic interventions must be tissue targeted so that whole-body fuel homeostasis is not adversely perturbed.
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PMID:Therapeutic potential of the mammalian pyruvate dehydrogenase kinases in the prevention of hyperglycaemia. 1247 89

A number of therapeutic targets are currently under investigation for inhibition of hepatic glucose production with small molecules. Antagonists of the glucagon receptor, glycogen phosphorylase, 11-beta-hydroxysteroid dehydrogenase-1 and fructose 1,6-bisphosphatase are, or have been, under evaluation in human clinical trials. Other strategies, including glucocorticoid receptor antagonists and carnitine palmitoyltransferase inhibitors, are supported by proof of principle studies in man as well as rodents. Several potential targets including glucose-6-phosphatase, glucose-6-phosphatase translocase, glycogen synthase kinase-3, adenosine receptor 2B antagonists, phosphoenolpyruvate carboxykinase and pyruvate dehydrogenase kinase, have been validated by compounds that are effective in animal models. Other targets like PGC-1a and CREB have initial validation support but no medicinal chemistry has been reported.
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PMID:Potential drug targets and progress towards pharmacologic inhibition of hepatic glucose production. 1257 Jul 14

Ingestion of carbohydrate during exercise may blunt the stimulation of fat oxidative pathways by raising plasma insulin and glucose concentrations and lowering plasma free fatty acid (FFA) levels, thereby causing a marked shift in substrate oxidation. We investigated the effects of a single 2-h bout of moderate-intensity exercise on the expression of key genes involved in fat and carbohydrate metabolism with or without glucose ingestion in seven healthy untrained men (22.7 +/- 0.6 yr; body mass index: 23.8 +/- 1.0 kg/m(2); maximal O(2) consumption: 3.85 +/- 0.21 l/min). Plasma FFA concentration increased during exercise (P < 0.01) in the fasted state but remained unchanged after glucose ingestion, whereas fat oxidation (indirect calorimetry) was higher in the fasted state vs. glucose feeding (P < 0.05). Except for a significant decrease in the expression of pyruvate dehydrogenase kinase-4 (P < 0.05), glucose ingestion during exercise produced minimal effects on the expression of genes involved in carbohydrate utilization. However, glucose ingestion resulted in a decrease in the expression of genes involved in fatty acid transport and oxidation (CD36, carnitine palmitoyltransferase-1, uncoupling protein 3, and 5'-AMP-activated protein kinase-alpha(2); P < 0.05). In conclusion, glucose ingestion during exercise decreases the expression of genes involved in lipid metabolism rather than increasing genes involved in carbohydrate metabolism.
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PMID:Glucose ingestion during exercise blunts exercise-induced gene expression of skeletal muscle fat oxidative genes. 1603 63

The effects of high-fat (HF) feeding on gene expression in the small intestine were examined using obesity-resistant A/J mice and obesity-prone C57BL/6J (B6) mice. Both strains of mice were maintained on low-fat (LF; 5% fat) or HF (30% fat) diets for 2 wk. Quantitative reverse transcription-PCR analysis revealed that lipid metabolism-related genes, including carnitine palmitoyltransferase (CPT) I, liver fatty acid binding protein, pyruvate dehydrogenase kinase-4, and NADP(+)-dependent cytosolic malic enzyme, were upregulated by HF feeding in both strains of mice. The upregulated gene expression levels were higher in A/J mice than in B6 mice, suggesting more active lipid metabolism in the small intestine of A/J mice. The prominent upregulation of the lipid metabolism-related genes were specific to the small intestine; the expression levels were little or unchanged in the liver, muscle, and white adipose tissue. The increase by HF feeding and predominant expression of the intestinal lipid metabolism-related genes in A/J mice were reflected in the enzyme activities; malic enzyme, CPT, and beta-oxidation activities were increased by HF feeding, and the upregulated malic enzyme and CPT activities were significantly higher in obesity-resistant A/J mice compared with those in obesity-prone B6 mice. These findings suggest that intestinal lipid metabolism is associated with susceptibility to obesity.
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PMID:Differential regulation of intestinal lipid metabolism-related genes in obesity-resistant A/J vs. obesity-prone C57BL/6J mice. 1682 57

Previous investigations show that intracerebroventricular administration of a potent inhibitor of fatty acid synthase, C75, increases the level of its substrate, malonyl-CoA, in the hypothalamus. The "malonyl-CoA signal" is rapidly transmitted to skeletal muscle by the sympathetic nervous system, increasing fatty acid oxidation, uncoupling protein-3 (UCP3) expression, and thus, energy expenditure. Here, we show that intracerebroventricular or intraperitoneal administration of C75 increases the number of mitochondria in white and red (soleus) skeletal muscle. Consistent with signal transmission from the hypothalamus by the sympathetic nervous system, centrally administered C75 rapidly (< or =2 h) up-regulated the expression (in skeletal muscle) of the beta-adrenergic signaling molecules, i.e., norepinephrine, beta3-adrenergic receptor, and cAMP; the transcriptional regulators peroxisomal proliferator activator regulator gamma coactivator 1alpha (PGC-1alpha) and estrogen receptor-related receptor alpha (ERRalpha); and the expression of key oxidative mitochondrial enzymes, including pyruvate dehydrogenase kinase, medium-chain length fatty acyl-CoA dehydrogenase, ubiquinone-cytochrome c reductase, cytochrome oxidase, as well as ATP synthase and UCP3. The role of PGC-1alpha in mediating these responses in muscle was assessed with C2C12 myocytes in cell culture. Consistent with the in vivo response, adenovirus-directed expression of PGC-1alpha in C2C12 muscle cells provoked the phosphorylation/inactivation and reduced expression of acetyl-CoA carboxylase 2, causing a reduction of the malonyl-CoA concentration. These effects, coupled with an increased carnitine palmitoyltransferase 1b, led to increased fatty acid oxidation. PGC-1alpha also increased the expression of ERRalpha, PPARalpha, and enzymes that support mitochondrial fatty acid oxidation, ATP synthesis, and thermogenesis, apparently mediated by an increased expression of UCP3.
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PMID:Hypothalamic malonyl-CoA triggers mitochondrial biogenesis and oxidative gene expression in skeletal muscle: Role of PGC-1alpha. 1703 Jul 88

PDK4 (pyruvate dehydrogenase kinase 4) regulates pyruvate oxidation through the phosphorylation and inhibition of the pyruvate dehydrogenase complex (PDC). PDC catalyzes the conversion of pyruvate to acetyl-CoA and is an important control point in glucose and pyruvate metabolism. PDK4 gene expression is stimulated by thyroid hormone (T(3)), glucocorticoids, and long chain fatty acids. The effects of T(3) on gene expression in the liver are mediated via the thyroid hormone receptor. Here, we have identified two binding sites for thyroid hormone receptor beta in the promoter of the rat PDK4 (rPDK4) gene. In addition, we have investigated the role of transcriptional coactivators and found that the PGC-1 alpha (peroxisome proliferator-activated receptor gamma coactivator) enhances the T(3) induction of rPDK4. Following T(3) administration, there is an increase in the association of PGC-1 alpha with the rPDK4 promoter. Interestingly, this increased association is with the proximal rPDK4 promoter rather than the distal region of the gene that contains the T(3) response elements. Administration of T(3) to hypothyroid rats elevated the abundance of PGC-1 alpha mRNA and protein in the liver. In addition, we observed greater association of PGC-1 alpha not only with the rPDK4 gene but also with phosphoenolpyruvate carboxykinase and CPT-1a (carnitine palmitoyltransferase 1a) genes. Knockdown of PGC-1 alpha in rat hepatocytes reduced the T(3) induction of PDK4, PEPCK, and CPT-1a genes. Our results indicate that T(3) regulates PGC-1 alpha abundance and association with hepatic genes, and in turn PGC-1 alpha is an important participant in the T(3) induction of selected genes.
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PMID:Regulation of pyruvate dehydrogenase kinase 4 (PDK4) by thyroid hormone: role of the peroxisome proliferator-activated receptor gamma coactivator (PGC-1 alpha). 1994 29

The delicate homeostatic balance between glucose and fatty acid metabolism in relation to whole-body energy regulation is influenced by mitochondrial function. We determined expression and regulation of mitochondrial enzymes including pyruvate dehydrogenase kinase (PDK) 4, PDK2, carnitine palmitoyltransferase 1b, and malonyl-coenzyme A decarboxylase in skeletal muscle from people with normal glucose tolerance (NGT) or type 2 diabetes mellitus (T2DM). Vastus lateralis biopsies were obtained from NGT (n = 79) or T2DM (n = 33) men and women matched for age and body mass index. A subset of participants participated in a 4-month lifestyle intervention program consisting of an unsupervised walking exercise. Muscle biopsies were analyzed for expression and DNA methylation status. Primary myotubes were derived from biopsies obtained from NGT individuals for metabolic studies. Cultured skeletal muscle was exposed to agents mimicking exercise activation for messenger RNA (mRNA) expression analysis. The mRNA expression of PDK4, PDK2, and malonyl-coenzyme A decarboxylase was increased in skeletal muscle from T2DM patients. Methylation of the PDK4 promoter was reduced in T2DM and inversely correlated with PDK4 expression. Moreover, PDK4 expression was positively correlated with body mass index, blood glucose, insulin, C peptide, and hemoglobin A(1c). A lifestyle intervention program resulted in increased PDK4 mRNA expression in NGT individuals, but not in those with T2DM. Exposure to caffeine or palmitate increased PDK4 mRNA in a cultured skeletal muscle system. Our findings reveal that skeletal muscle expression of PDK4 and related genes regulating mitochondrial function reflects alterations in substrate utilization and clinical features associated with T2DM. Furthermore, hypomethylation of the PDK4 promoter in T2DM coincided with an impaired response of PDK4 mRNA after exercise.
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PMID:Mitochondrial regulators of fatty acid metabolism reflect metabolic dysfunction in type 2 diabetes mellitus. 2181 45


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