Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.2 (PDK1)
 2,238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Cytosolic and mitochondrial ATP and ADP concentrations of liver cells isolated from normal fed, starved and diabetic rats were determined. 2. The cytosolic ATP/ADP ratio was 6,9 and 10 in normal fed, starved and diabetic rats respectively. 3. The mitochondrial ATP/ADP ratio was 2 in normal and diabetic rats and 1.6 in starved rats. 4. Adenosine increased the cytosolic and lowered the mitochondrial ATP/ADP ratio, whereas atractyloside had the opposite effect. 5. Incubation of the hepatocytes with fructose, glycerol or sorbitol led to a fall in the ATP/ADP ratio in both the cytosolic and the mitochondrial compartment. 6. The interrelationship between the mitochondrial ATP/ADP ratio and the phosphorylation state of pyruvate dehydrogenase in intact cells was studied. 7. In hepatocytes isolated from fed rats an inverse correlation between the mitochondrial ATP/ADP ratio and the active form of pyruvate dehydrogenase (pyruvate dehydrogenase a) was demonstrable on loading with fructose, glycerol or sorbitol. 8. No such correlation was obtained with pyruvate or dihydroxyacetone. For pyruvate, this can be explained by inhibition of pyruvate dehydrogenase kinase. 9. Liver cells isolated from fed animals displayed pyruvate dehydrogenase a activity twice that found in vivo. Physiological values were obtained when the hepatocytes were incubated with albumin-oleate, which also yielded the highest mitochondrial ATP/ADP ratio.
 ...
PMID:Phosphorylation state of cytosolic and mitochondrial adenine nucleotides and of pyruvate dehydrogenase in isolated rat liver cells. 13 78

1. Monochloroacetate, dichloroacetate, trichloroacetate, difluoroacetate, 2-chloropropionate, 2,2'-dichloropropionate and 3-chloropropionate were inhibitors of pig heart pyruvate dehydrogenase kinase. Dichloroacetate was also shown to inhibit rat heart pyruvate dehydrogenase kinase. The inhibition was mainly non-competitive with respect to ATP. The concentration required for 50% inhibition was approx. 100mum for the three chloroacetates, difluoroacetate and 2-chloropropionate and 2,2'-dichloropropionate. Dichloroacetamide was not inhibitory. 2. Dichloroacetate had no significant effect on the activity of pyruvate dehydrogenase phosphate phosphatase when this was maximally activated by Ca(2+) and Mg(2+). 3. Dichloroacetate did not increase the catalytic activity of purified pig heart pyruvate dehydrogenase. 4. Dichloroacetate, difluoroacetate, 2-chloropropionate and 2,2'-dichloropropionate increased the proportion of the active (dephosphorylated) form of pyruvate dehydrogenase in rat heart mitochondria with 2-oxoglutarate and malate as respiratory substrates. Similar effects of dichloroacetate were shown with kidney and fat-cell mitochondria. Glyoxylate, monochloroacetate and dichloroacetamide were inactive. 5. Dichloroacetate increased the proportion of active pyruvate dehydrogenase in the perfused rat heart, isolated rat diaphragm and rat epididymal fat-pads. Difluoroacetate and dichloroacetamide were also active in the perfused heart, but glyoxylate, monochloroacetate and trichloroacetate were inactive. 6. Injection of dichloroacetate into rats starved overnight led within 60 min to activation of pyruvate dehydrogenase in extracts from heart, psoas muscle, adipose tissue, kidney and liver. The blood concentration of lactate fell within 15 min to reach a minimum after 60 min. The blood concentration of glucose fell after 90 min and reached a minimum after 120 min. There was no significant change in plasma glycerol concentration. 7. In epididymal fatpads dichloroacetate inhibited incorporation of (14)C from [U-(14)C]glucose, [U-(14)C]fructose and from [U-(14)C]lactate into CO(2) and glyceride fatty acid. 8. It is concluded that the inhibition of pyruvate dehydrogenase kinase by dichloroacetate may account for the activation of pyruvate dehydrogenase and pyruvate oxidation which it induces in isolated rat heart and diaphragm muscles, subject to certain assumptions as to the distribution of dichloroacetate across the plasma membrane and the mitochondrial membrane. 9. It is suggested that activation of pyruvate dehydrogenase by dichloroacetate could contribute to its hypoglycaemic effect by interruption of the Cori and alanine cycles. 10. It is suggested that the inhibitory effect of dichloroacetate on fatty acid synthesis in adipose tissue may involve an additional effect or effects of the compound.
 ...
PMID:Mechanism of activation of pyruvate dehydrogenase by dichloroacetate and other halogenated carboxylic acids. 447 69

Insulin provokes rapid changes in phospholipid metabolism and thereby generates biologically active lipids that serve as intracellular signaling factors that regulate glucose transport and glycogen synthesis. These changes include: (i) activation of phosphatidylinositol 3-kinase (PI3K) and production of PIP3; (ii) PIP3-dependent activation of atypical protein kinase Cs (PKCs); (iii) PIP3-dependent activation of PKB; (iv) PI3K-dependent activation of phospholipase D and hydrolysis of phosphatidylcholine with subsequent increases in phosphatidic acid (PA) and diacylglycerol (DAG); (v) PI3K-independent activation of glycerol-3-phosphate acylytansferase and increases in de novo synthesis of PA and DAG; and (vi) activation of DAG-sensitive PKCs. Recent findings suggest that atypical PKCs and PKB serve as important positive regulators of insulin-stimulated glucose metabolism, whereas mechanisms that result in the activation of DAG-sensitive PKCs serve mainly as negative regulators of insulin signaling through PI3K. Atypical PKCs and PKB are rapidly activated by insulin in adipocytes, liver, skeletal muscles, and other cell types by a mechanism requiring PI3K and its downstream effector, 3-phosphoinositide-dependent protein kinase-1 (PDK-1), which, in conjunction with PIP3, phosphorylates critical threonine residues in the activation loops of atypical PKCs and PKB. PIP3 also promotes increases in autophosphorylation and allosteric activation of atypical PKCs. Atypical PKCs and perhaps PKB appear to be required for insulin-induced translocation of the GLUT 4 glucose transporter to the plasma membrane and subsequent glucose transport. PKB also appears to be the major regulator of glycogen synthase. Together, atypical PKCs and PKB serve as a potent, integrated PI3K/PDK-1-directed signaling system that is used by insulin to regulate glucose metabolism.
 ...
PMID:Insulin-sensitive phospholipid signaling systems and glucose transport. Update II. 1136 19

The increase in skeletal muscle pyruvate dehydrogenase kinase (PDK) activity was measured in skeletal muscle of six healthy males after a eucaloric high-fat/low-carbohydrate (HF/LC; 5% carbohydrate, 73% fat, and 22% protein of total energy intake) diet compared with a standardized prediet (50% carbohdyrate, 30% fat, and 21% protein). Biopsies were obtained from the vastus lateralis muscle after 3 days on the prediet (day 0) and after 1, 2, and 3 days of the HF/LC diet. Intact mitchondria were extracted from fresh muscle and analyzed for PDK activity and Western blotting of PDK2 and PDK4 protein. A second biopsy was taken at each time point and frozen for Northern blot analysis of PDK2 and PDK4 mRNAs. PDK activity increased in a linear fashion over the 3-day HF/LC diet and was significantly higher than control by 1 day. PDK activity was 0.09 +/- 0.03, 0.18 +/- 0.05, 0.30 +/- 0.07, and 0.37 +/- 0.09 min(-1) at 0, 1, 2, and 3 days, respectively. PDK4 protein and mRNA increased maximally by day 1, and PDK2 protein and mRNA were unaffected by the HF/LC diet. Resting respiratory exchange ratios decreased after 1 day of the HF/LC diet (from 0.79 +/- 0.02 to 0.72 +/- 0.02) and remained depressed throughout the 3-day dietary intervention (0.68 +/- 0.01). The immediate shift to fat utilization was accompanied by increased blood glycerol, beta-hydroxybutyrate, and plasma free fatty acid concentrations. These results suggest that the continuing increase in PDK activity over the 3-day HF/LC diet is not due to increasing PDK protein beyond 1 day. This could be due to the contribution of another isoform to the total PDK activity or to a continual increase in PDK4 or PDK2 specific activity.
 ...
PMID:Human skeletal muscle PDH kinase activity and isoform expression during a 3-day high-fat/low-carbohydrate diet. 1170 28

Fasting forces adaptive changes in whole body and skeletal muscle metabolism that increase fat oxidation and decrease the oxidation of carbohydrate. We tested the hypothesis that 40 h of fasting would decrease pyruvate dehydrogenase (PDH) activity and increase PDH kinase (PDK) isoform mRNA expression in human skeletal muscle. The putative transcriptional activators of PDK isozymes, peroxisome proliferator-activated receptor-alpha (PPAR-alpha) protein, and forkhead homolog in rhabdomyosarcoma (FKHR) mRNA were also measured. Eleven healthy adults fasted after a standard meal (25% fat, 60% carbohydrate, 15% protein) with blood and skeletal muscle samples taken at 3, 15, and 40 h postprandial. Fasting increased plasma free fatty acid, glycerol, and beta-hydroxybutyrate concentrations and decreased glucose and insulin concentrations. PDH activity decreased from 0.88 +/- 0.11 mmol acetyl-CoA. min(-1). kg wet muscle wt(-1) at 3 h to 0.62 +/- 0.10 (P = not significant) and 0.39 +/- 0.06 (P < 0.05) mmol. min(-1). kg wet mass(-1) after 15 and 40 h of fasting. Although all four PDK isoforms were expressed in human skeletal muscle, PDK-2 and -4 mRNA were the most abundant. PDK-1 and -3 mRNA abundance was approximately 1 and 15% of the PDK-2 and -4 levels, respectively. The 40-h fast had no effect on PDK-1, -2, and -3 mRNA expression. PDK-4 mRNA was significantly increased approximately 3-fold after 15 h and approximately 14-fold after 40 h of fasting. Skeletal muscle PPAR-alpha protein and FKHR mRNA abundance were unaffected by the fast. The results suggest that decreased PDH activation after 40 h of fasting may have been a function of the large increase in PDK-4 mRNA expression and possible subsequent increase in PDK protein and activity. The changes in PDK-4 expression and PDH activity did not coincide with increases in the transcriptional activators PPAR-alpha and FKHR.
 ...
PMID:Pyruvate dehydrogenase activation and kinase expression in human skeletal muscle during fasting. 1496 24

We tested the hypothesis that a high-fat diet (75% fat; 5% carbohydrates; 20% protein), for which 15% of the fat content was substituted with n-3 fatty acids, would not exhibit the diet-induced increase in pyruvate dehydrogenase kinase (PDK) activity, which is normally observed in human skeletal muscle. The fat content was the same in both the regular high-fat diet (HF) and in the n-3-substituted diet (N3). PDK activity increased after both high-fat diets, but the increase was attenuated after the N3 diet (0.051 +/- 0.007 and 0.218 +/- 0.047 min(-1) for pre- and post-HF, respectively; vs. 0.073 +/- 0.016 and 0.133 +/- 0.032 min(-1) for pre- and post-N3, respectively). However, the active form of pyruvate dehydrogenase (PDHa) activity decreased to a similar extent in both conditions (0.93 +/- 0.17 and 0.43 +/- 0.09 mmol/kg wet wt pre- and post-HF; vs. 0.87 +/- 0.19 and 0.39 +/- 0.05 mmol/kg wet wt pre- and post-N3, respectively). This suggested that the difference in PDK activity did not affect PDHa activation in the basal state, and it was regulated by intramitochondrial effectors, primarily muscle pyruvate concentration. Muscle glycogen content was consistent throughout the study, before and after both diet conditions, whereas muscle glucose-6-phosphate, glycerol-3-phosphate, lactate, and pyruvate were decreased after the high-fat diets. Plasma triglycerides decreased after both high-fat diets but decreased to a greater extent after the N3, whereas plasma free fatty acids increased after both diets, but to a lesser extent after the N3. In summary, PDK activity is decreased after a high-fat diet that is rich in n-3 fatty acids, although PDHa activity was unaltered. In addition, our data demonstrated that the hypolipidemic effect of n-3 fatty acids occurs earlier (3 days) than previously reported and is evident even when the diet has 75% of its total energy derived from fat.
 ...
PMID:Elevated n-3 fatty acids in a high-fat diet attenuate the increase in PDH kinase activity but not PDH activity in human skeletal muscle. 1559 5

Reduced carbohydrate (CHO) availability after exercise has a potent influence on the regulation of substrate metabolism, but little is known about the impact of fat availability and/or energy deficit on fuel metabolism when dietary CHO availability is not reduced. The purpose of this study was to determine the influence of a postexercise energy deficit, independent of CHO availability, on plasma substrate concentrations and substrate oxidation. Seven moderately trained men (peak oxygen uptake: 56 +/- 2 ml.kg(-1).min(-1)) performed exhaustive cycling exercise on two separate occasions. The two trials differed only by the meals ingested after exercise: 1) a high-fat diet designed to maintain energy balance or 2) a low-fat diet designed to elicit energy deficit. The CHO and protein contents of the diets were identical. The next morning, we measured plasma substrate and insulin concentrations and CHO oxidation, and we obtained muscle biopsies from the vastus lateralis for measurement of pyruvate dehydrogenase kinase (PDK)-2 and PDK-4 mRNA expression by using RT-PCR. Despite identical blood glucose (5.0 +/- 0.1 and 4.9 +/- 0.1 mM) and insulin (7.9 +/- 1.1 and 8.4 +/- 0.9 microU/ml) concentrations, plasma fatty acid and glycerol concentrations were elevated three- to fourfold during energy deficit compared with energy balance and CHO oxidation was 40% lower (P < 0.01) the morning after energy deficit compared with energy balance (328 +/- 69 and 565 +/- 89 micromol/min). The lower CHO oxidation was accompanied by a 7.3 +/- 2.5-fold increase in PDK-4 mRNA expression after energy deficit (P < 0.05), whereas PDK-2 mRNA was similar between the trials. In conclusion, energy deficit increases fatty acid availability, increases PDK-4 mRNA expression, and suppresses CHO oxidation even when dietary CHO content is not reduced.
 ...
PMID:Energy deficit without reducing dietary carbohydrate alters resting carbohydrate oxidation and fatty acid availability. 1560 91

In this study, we examined whether the increased availability of lipids in blood resulting from two types of diet manipulation regulated metabolic gene expression in the skeletal muscle of rats. Feeding for 4 wk on an isocaloric-sucrose or a hypercaloric-fat diet increased plasma TAG in the fed condition by increments of 70 and 40%, respectively, and increased fasting insulinemia (approximately 3-fold) compared with a starch diet. The fat diet impaired glucose tolerance and caused obesity, whereas sucrose-fed rats maintained their normal weight. We analyzed the expression of genes that regulate the exogenous FA supply (LPL, FAT/CD36, FATP1), synthesis (ACC1), glucose (GLUT4, GLUT1, HK2, GFAT1, glycogen phosphorylase) or glycerol (glycerol kinase) provision, or substrate choice for oxidation (PDK4) in gastrocnemius and soleus muscles at the end of the glucose tolerance test. LPL, FAT/CD36, FATP1, PDK4, and GLUT4 mRNA as well as glycogen phosphorylase and glycerol kinase activity levels in both muscles were unchanged by the diets. Increased mRNA levels of GLUT1 (1.6- and 2.6-fold, respectively) and GFAT1 (about 1.7-fold) in gastrocnemius, and of ACC1 (about 1.5-fold) in soleus, were found in both the sucrose and fat groups. In the fat group, HK2 mRNA was also higher (1.8-fold) in the gastrocnemius. Both sucrose and saturated-fat diets prompted hyperinsulinemia and hyperlipemia in rats. These metabolic disturbances did not alter the expression of LPL, FAT/CD36, FATP1, PDK4, and GLUT4 genes or glycogen phosphorylase and glycerol kinase activity levels in either analyzed muscle. Instead, they were linked to the coordinated upregulation in gastrocnemius of genes that govern glucose uptake and the hexosamine pathway, namely, GLUT1 and GFAT1, which might contribute to insulin resistance.
 ...
PMID:Effect of sucrose and saturated-fat diets on mRNA levels of genes limiting muscle fatty acid and glucose supply in rats. 1655 72

Endurance exercise transiently increases the mRNA of key regulatory proteins involved in skeletal muscle metabolism. During prolonged exercise and subsequent recovery, circulating plasma fatty acid (FA) concentrations are elevated. The present study therefore aimed to determine the sensitivity of key metabolic genes to FA exposure, assessed in vitro using L6 myocytes and secondly, to measure the expression of these same set of genes in vivo, following a single exercise bout when the post-exercise rise in plasma FA is abolished by acipimox. Initial studies using L6 myotubes demonstrated dose responsive sensitivity for both PDK4 and PGC-1alpha mRNA to acute FA exposure in vitro. Nine active males performed two trials consisting of 2 h exercise, followed by 2 h of recovery. In one trial, plasma FA availability was reduced by the administration of acipimox (LFA), a pharmacological inhibitor of adipose tissue lipolysis, and in the second trial a placebo was provided (CON). During the exercise bout and during recovery, the rise in plasma FA and glycerol was abolished by acipimox treatment. Following exercise the mRNA abundance of PDK4 and PGC-1alpha were elevated and unaffected by either acipimox or placebo. Further analysis of skeletal muscle gene expression demonstrated that the CPT I gene was suppressed in both trials, whilst UCP-3 gene was only modestly regulated by exercise alone. Acipimox ingestion did not alter the response for both CPT I and UCP-3. Thus, this study demonstrates that the normal increase in circulating concentrations of FA during the later stages of exercise and subsequent recovery is not required to induce skeletal muscle mRNA expression of several proteins involved in regulating substrate metabolism.
 ...
PMID:Reduced plasma free fatty acid availability during exercise: effect on gene expression. 1718 95

Corticosteroids (CS) effects on insulin resistance related genes in rat skeletal muscle were studied. In our acute study, adrenalectomized (ADX) rats were given single doses of 50 mg/kg methylprednisolone (MPL) intravenously. In our chronic study, ADX rats were implanted with Alzet mini-pumps giving zero-order release rates of 0.3 mg/kg/h MPL and sacrificed at various times up to 7 days. Total RNA was extracted from gastrocnemius muscles and hybridized to Affymetrix GeneChips. Data mining and literature searches identified 6 insulin resistance related genes which exhibited complex regulatory pathways. Insulin receptor substrate-1 (IRS-1), uncoupling protein 3 (UCP3), pyruvate dehydrogenase kinase isoenzyme 4 (PDK4), fatty acid translocase (FAT) and glycerol-3-phosphate acyltransferase (GPAT) dynamic profiles were modeled with mutual effects by calculated nuclear drug-receptor complex (DR(N)) and transcription factors. The oscillatory feature of endothelin-1 (ET-1) expression was depicted by a negative feedback loop. These integrated models provide testable quantitative hypotheses for these regulatory cascades.
 ...
PMID:Pharmacodynamic/pharmacogenomic modeling of insulin resistance genes in rat muscle after methylprednisolone treatment: exploring regulatory signaling cascades. 1978 81


1 2 3 Next >>