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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study evaluated the substrate competition between fatty acids (FA) and glucose in the kidney in vivo in relation to the operation of the "glucose-FA" and "reverse glucose-FA" cycles. In fed rats, neither inhibition of adipocyte lipolysis by 5-methylpyrazole-3-carboxylic acid (MPCA) nor inhibition of mitochondrial long-chain FA oxidation by 2-tetradecylglycidate (TDG) influenced the renal ratio of free/acylated carnitine or the percentage of total renal pyruvate dehydrogenase complex (PDHC) in the active (dephosphorylated) form (PDHa). The additional provision of glucose, a precursor for the synthesis of malonyl-coenzyme A (coA), did not influence renal PDHa activity or the renal ratio of free to acylated carnitine, implying that FA oxidation is maximally suppressed in the fed state. A reverse glucose-FA cycle may therefore be important in suppressing renal FA oxidation in the fed state. After 48 hours of starvation, MPCA and TDG decreased short- and long-chain acylcarnitine concentrations (40% to 50%, P < .01) and elevated the renal ratio of free/acylated carnitine (2.5-fold, P < .001, and 3.3-fold, P < .001, respectively), indicating that FA oxidation is increased after starvation. Despite suppression of renal FA oxidation, renal PDHa activity in 48-hour starved rats was only partially restored by treatment with MPCA or TDG. The additional administration of glucose did not remedy this. The failure to reverse completely the effects of prolonged starvation in suppressing PDHC activity by acute inhibition of FA oxidation suggests additional regulatory mechanisms that dampen the PDHC response to acute changes in substrate supply. Estimations of PDH kinase (PDK) activity in renal mitochondria showed a significant 1.7-fold stable increase (P < .01) after 48 hours of starvation. Analysis of PDK pyruvate sensitivity in renal mitochondria incubated with respiratory substrate (5 mmol/L 2-oxoglutarate/0.5 mmol/L L-malate) showed that the pyruvate concentration required for 50% activation was substantially decreased by starvation. Enzyme-linked immunosorbent assay (ELISA) analysis over a range of PDHC activities demonstrated that increased PDK activity was concomitant with a significant (at least P < .01) 1.8-fold increase in the protein expression of the ubiquitously expressed PDK isoform, PDK2. We hypothesize that changes in protein expression and activity of individual PDK isoforms may dictate the renal response to incoming FA lesterification v oxidation) through modulation of the relationship between glycolytic flux and PDHC activity, and thus the provision of precursor for malonyl-coA production.
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PMID:Substrate interactions in the short- and long-term regulation of renal glucose oxidation. 1038 Nov 44

We studied the effects of exercise training on the activity of the pyruvate dehydrogenase (PDH) complex in rat gastrocnemius muscle (experiment 1) and the response of the complex to glucose and insulin infusion (euglycemic clamp) in trained and sedentary rats (experiment 2). In experiment 1, half of the rats were randomly allocated as sedentary animals and the other half were trained by voluntary running exercise for 8 weeks. The total activity of the PDH complex was not affected by exercise training, and the activity state (proportion of the active form) of the PDH complex was decreased from 15.0%+/-2.4% to 7.5%+/-1.1% by exercise training. The activity of 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase ([3-HADH] an enzyme in beta-oxidation) was significantly higher in trained versus sedentary rats. In experiment 2, sedentary and trained rats were starved for 24 hours before performing the euglycemic clamp. Glucose and insulin infusion was performed by a euglycemic clamp (insulin infusion rate, 6 mU/kg/min) for 90 minutes. The PDH complex was inactivated to less than 1% in both sedentary and trained rats after 24 hours of starvation. The glucose infusion rate (GIR) during the euglycemic clamp was higher in trained versus sedentary rats. The euglycemic clamp resulted in activation of the PDH complex in both sedentary and trained rats, but the response of the PDH complex to the euglycemic clamp was significantly higher in trained rats (5.8%+/-0.5%) than in sedentary rats (2.9%+/-0.5%). These results suggest that exercise training promotes fatty acid oxidation in association with suppression of glucose oxidation in skeletal muscle under resting conditions, but increases the rate of carbohydrate oxidation when glucose flux into muscle cells is stimulated by insulin.
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PMID:Insulin activation of pyruvate dehydrogenase complex is enhanced by exercise training. 1042 Dec 27

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.
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PMID:Mechanism responsible for inactivation of skeletal muscle pyruvate dehydrogenase complex in starvation and diabetes. 1042 78

It has been suggested that Escherichia coli can resist aerobic, glucose-starvation conditions by switching rapidly from an aerobic to a fermentative metabolism, thereby preventing the production by the respiratory chain of reactive oxygen species (ROS) that can damage cellular constituents. In contrast, it has been reported that E. coli cannot resist aerobic, phosphate (Pi)-starvation conditions, probably because of the maintenance of an aerobic metabolism and the continuous production of ROS. This paper presents evidence that E. coli cells starved for Pi under aerobic conditions indeed maintain an active aerobic metabolism for about 3 d, which allows the complete degradation of exogenous nutrients such as arginine (metabolized probably to putrescine via the SpeA-initiated pathway) and glucose (metabolized notably to acetate), but cell viability is not significantly affected because of the protection afforded against ROS through the expression of the RpoS and LexA regulons. The involvement of the LexA-controlled RuvAB and RecA proteins with the RecG and RecBCD proteins in metabolism and cell viability implies that DNA double-strand breaks (DSB), and thus hydroxyl radicals that normally generate this type of damage, are produced in Pi-starved cells. It is shown that induction of the LexA regulon, which helps protect Pi-starved cells, is totally prevented by introduction of a recB mutation, which indicates that DSB are actually the main DNA lesion generated in Pi-starved cells. The requirement of RpoS for survival of cells starved for Pi may thus be explained by the role played by various RpoS-controlled gene products such as KatE, KatG and Dps in the protection of DNA against ROS. In the same light, the degradation of arginine and threonine may be accounted for by the synthesis of polyamines (putrescine and spermidine) that protect nucleic acids from ROS. Besides LexA and RpoS, a third global regulator, the nucleoid-associated protein H-NS, is also shown to play a key role in Pi-starved cells. Through a modulation of the metabolism during Pi starvation, H-NS may perform two complementary tasks: it helps maintain a rapid metabolism of glucose and arginine, probably by favouring the activity of aerobic enzymes such as the NAD-dependent pyruvate dehydrogenase complex, and it may enhance the cellular defences against ROS which are then produced by increasing RpoS activity via the synthesis of acetate and presumably homoserine lactone.
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PMID:Role of Escherichia coli RpoS, LexA and H-NS global regulators in metabolism and survival under aerobic, phosphate-starvation conditions. 1043 94

The effect of hypoxia on root development and carbon metabolism was studied using potato (Solanum tuberosum L.) plants as a model system. Hypoxia led to a cessation of root elongation, and finally to the death of meristematic cells. These changes were accompanied by a 4- to 5-fold accumulation of hexoses, suggesting that insufficient carbohydrate supply was not the cause of cell death. In addition, prolonged hypoxia (96 h) resulted in a 50% increase in activity of most glycolytic enzymes studied and the accumulation of glycerate-3-phosphate and phosphoenolpyruvate. This indicates that endproduct utilisation may restrict metabolic flux through glycolysis. As expected, the activities of alcohol dehydrogenase (EC 1.1.1.1) and pyruvate decarboxylase (EC 4.1.1.17) increased during hypoxia. Apart from the enzymes of ethanolic fermentation the activity of sucrose synthase (SuSy; EC 2.4.1.13) was enhanced. To investigate the in-vivo significance of this increase, transgenic plants with reduced SuSy activity were analysed. Compared to untransformed controls, transgenic plants showed a reduced ability to resume growth after re-aeration, emphasising the crucial role of SuSy in the toleration of hypoxia. Surprisingly, analysis of glycolytic intermediates in root extracts from SuSy antisense plants revealed no change as compared to wildtype plants. Therefore, limitation of glycolysis is most likely not responsible for the observed decreased ability for recovery after prolonged oxygen starvation. We assume that the function of SuSy during hypoxia might be to channel excess carbohydrates into cell wall polymers for later consumption rather than fuelling glycolysis.
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PMID:Sucrose synthase activity does not restrict glycolysis in roots of transgenic potato plants under hypoxic conditions 1059 31

We isolated a mouse homologue cDNA of pyruvate dehydrogenase (PDH) kinase 4 (PDK4) with differential mRNA display as an up-regulated gene in the hypertrophied ventricles of juvenile visceral steatosis (JVS) mice with systemic carnitine deficiency. The PDK4 mRNA level was 5 times higher in JVS mice than in control mice under fed conditions. After 24 h starvation, this level increased to 20 times in JVS and 7 times in control, compared with the control fed level. On the other hand, carnitine administration reduced the high level of PDK4 mRNA in JVS mice to the control fed level. In control mice, the change in PDK4 mRNA was inversely correlated with the change in PDH activity. In JVS mice, however, the PDK4 mRNA level was not always correlated with the active-form PDH level.
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PMID:Pyruvate dehydrogenase kinase 4 mRNA is increased in the hypertrophied ventricles of carnitine-deficient juvenile visceral steatosis (JVS) mice. 1060 98

Enterococcus faecalis induces the synthesis of at least 42 proteins during 24 h of glucose starvation. Because of its induction during carbohydrate and complete starvation (incubation in tap water) and CdCl(2) and bile salts stresses, one of these proteins (Gls24) was qualified as a "general stress protein" and was analyzed at the molecular level. Its corresponding gene, gls24, seems to be the penultimate gene of an operon composed, altogether, of six open reading frames (ORFs). The ORF preceding gls24 (orf4) showed very strong identity with gls24. The deduced polypeptides of these two genes showed similarity with a 20-kDa hypothetical protein from Lactococcus lactis and an alkaline stress protein from Staphylococcus aureus with no previously known biological significance. Data from the operon sequence and Northern analysis led to the conclusions that (i) gls24 possesses its own promoter which is especially induced at the onset of starvation and (ii) the operon promoter is stress inducible in exponential-phase cells. A mutation in the gls24 gene led to a severe reduction of growth rate and reduction of survival against 0.3% bile salts in the 24-h-starved cells compared to the wild-type strain. Moreover, the chain length of the mutant is significantly reduced during growth. These results argue strongly for a role of the protein Gls24 and/or GlsB in morphological changes and in stress tolerance in E. faecalis. Comparison of two-dimensional protein gels from wild-type cells with those from gls24 mutant cells revealed a pleiotropic effect of the mutation on gene expression. At least nine proteins were present in larger amounts in the mutant. For six of them, the corresponding N-terminal microsequence has been obtained. Three of these sequences map in genes coding for L-lactate dehydrogenase, lipoamide dehydrogenase, and pyruvate decarboxylase, all involved in pyruvate metabolism.
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PMID:Inactivation of the stress- and starvation-inducible gls24 operon has a pleiotrophic effect on cell morphology, stress sensitivity, and gene expression in Enterococcus faecalis. 1091 85

Covalent modification of the pyruvate dehydrogenase complex provides an important regulatory mechanism for controlling the disposal of glucose and other compounds metabolized to pyruvate. Regulation of the complex by this mechanism is achieved in part by tissue-specific expression of the genes encoding isoenzymes of pyruvate dehydrogenase kinase (PDK). Starvation is known from our previous work to increase PDK activity of heart and skeletal muscle by increasing the amount of PDK isoenzyme 4 (PDK4) present in these tissues. This study demonstrates that increased expression of both PDK4 and PDK2 occurs in rat liver, kidney, and lactating mammary gland in response to starvation. PDK4 and PDK2 message levels were also increased by starvation in the two tissues examined (liver and kidney), suggesting enhancement of gene transcription. Changes in PDK2 message and protein were of similar magnitude, but changes in PDK4 message were greater than those in PDK4 protein, suggesting regulation at the level of translation. In contrast to these tissues, starvation had little or no effect on PDK2 and PDK4 protein in brain, white adipose tissue, and brown adipose tissue. Nevertheless, PDK4 message levels were significantly increased in brain and white adipose tissue by starvation. The findings of this study indicate that increased expression of PDK isoenzymes is an important mechanism for bringing about inactivation of the pyruvate dehydrogenase complex during starvation in many but not all tissues of the body. The absence of this mechanism preserves the capacity of neuronal tissue to utilize glucose for energy during starvation.
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PMID:Starvation increases the amount of pyruvate dehydrogenase kinase in several mammalian tissues. 1101 13

Contrary to common concepts, the brain in Alzheimer's disease (AD) does not follow a suicide but a rescue program. Widely shared features of metabolism in starvation, hibernation and various conditions of energy deprivation, e.g. ischemia, allow the definition of a deprivation syndrome which is a phylogenetically conserved adaptive response to energetic stress. It is characterized by hypometabolism, oxidative stress and adjustments of the glucose-fatty acid cycle. Cumulative evidence suggests that the brain in aging and AD actively adapts to the progressive fuel deprivation. The counterregulatory mechanisms aim to preserve glucose for anabolic needs and promote the oxidative utilization of ketone bodies. The agent mediating the metabolic switch is soluble Abeta which inhibits glucose utilization and stimulates ketone body utilization at various levels. These processes, which are initiated during normal aging, include inhibition of pro-glycolytic neurohormones, cholinergic transmission, and pyruvate dehydrogenase, the key transmitter and effector systems regulating glucose metabolism. Hormonal and effector systems which promote ketone body utilization, such as glucocorticosteroid and galanin activity, GABAergic transmission, nitric oxide, lipid transport, Ca2+ elevation, and ketone body metabolizing enzymes, are enhanced. A multitude of risk factors feed into this pathophysiological cascade at a variety of levels. Taking into account its pleiotropic regulatory actions in the deprivation response, a new name for Abeta is suggested: deprivin. On the other hand, cumulative evidence, taken together compelling, suggests that senile plaques are the dump rather than the driving force of AD. Moreover, the neurotoxic action of fibrillar Abeta is a likely in vitro artifact but does not contribute significantly to the in vivo pathophysiological events. This archaic program, conserved from bacteria to man, aims to ensure the survival of a deprived organism and controls such divergent processes as sporulation, hibernation, aging and aging-related diseases. In contrast to the immature brain, ketone body utilization of the aged brain is no longer sufficient to meet the energetic demands and is later supplemented by lactate, thus recapitulating in reverse order the sequential fuel utilization of the immature brain. The transduction pathways which operate to switch metabolism also convey the programming and balancing of the de-/redifferentiation/apoptosis cell cycle decisions. This encompasses the reiteration of developmental processes such as transcription factor activation, tau hyperphosphorylation, and establishment of growth factor independence by means of Ca2+ set point shift. Thus, the increasing energetic insufficiency results in the progressive centralization of metabolic activity to the neuronal soma, leading to pruning of the axonal/dendritic trees, loss of neuronal polarity, downregulation of neuronal plasticity and, eventually, depending on the Ca2+ -energy-redox homeostasis, degeneration of vulnerable neurons. Finally, it is outlined that genetic (e.g. Down's syndrome, APP and presenilin mutations and apoE4) and environmental risk factors represent progeroid factors which accelerate the aging process and precipitate the manifestation of AD as a progeroid systemic disease. Aging and AD are related to each other by threshold phenomena, corresponding to stage 2, the stage of resistance, and stage 3, exhaustion, of a metabolic stress response.
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PMID:A unifying hypothesis of Alzheimer's disease. IV. Causation and sequence of events. 1106 71

The principle substrate for brain metabolism is glucose, which provides both energy and the carbon skeletons of glutamate and glutamine, via the TCA cycle. The existence of two distinct cerebral metabolic compartments, neurons and glia, involved in glutamate and glutamine synthesis, respectively, is a widely accepted concept. In previous work, the relative glucose flux via pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC) in adult rabbit brain, using 13C NMR isotopomer analysis of glutamate and glutamine, was quantified. In this work, manifestation of cerebral compartmentation in the near-term fetal rabbit was investigated, using the above approach. Following infusion of [U-13C]glucose into maternal circulation (1 mg/kg per min) for 60-70 min, fetal brains were excised and brain extracts were studied by 13C NMR. The labelling patterns of fetal cerebral metabolites differed from those observed in the young adult brain. The most significant differences were found for glutamine labelling patterns. We suggested that these differences are a result of increased utilization of non-labeled fuels, mainly beta-hydroxybutyrate (beta-HBA) in the glia, the site of glutamine synthesis. In addition, we have shown that acute exposure to elevated beta-HBA levels leads to increased uptake, but not utilization, into the fetal rabbit brain; no increase in uptake is observed in the adult brain. We have also demonstrated that during short-term starvation, although no changes are detected in plasma and cerebral glucose levels in the fetal and young adult brain, amino acid levels and energy metabolism are altered in the young adult brain.
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PMID:Energy fuel utilization by fetal versus young rabbit brain: a 13C MRS isotopomer analysis of [U-(13)C]glucose metabolites. 1127 79


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