scholarly journals Activities of hexokinase, phosphofructokinase, 3-oxo acid coenzyme A-transferase and acetoacetyl-coenzyme A thiolase in nervous tissue from vertebrates and invertebrates

1973 ◽  
Vol 134 (1) ◽  
pp. 97-101 ◽  
Author(s):  
P. H. Sugden ◽  
E. A. Newsholme
Keyword(s):  
Nervous Tissue ◽  
Ketone Body ◽  
Glucose Utilization ◽  
Coenzyme A ◽  
Ketone Bodies ◽  
Animal Kingdom ◽  
Coa Transferase ◽  
Utilization Pathway ◽  
The Brain

1. The maximum activities of hexokinase and phosphofructokinase in nervous tissue from 18 different animals from different phyla range from 5.1 to 17.6 and from 24.0μmol/min per g fresh wt. respectively. In any one tissue the activities of these two enzymes are, in general, very similar. The rate of glucose utilization by the brain in vivo is much lower than the activities of hexokinase or phosphofructokinase. It is suggested that the high activities of these enzymes indicate a capacity for glycolysis which may be used by the brain during hypoxia or during conditions of extreme neuronal activity. 2. The activities of 3-oxo acid CoA-transferase and acetoacetyl-CoA thiolase in the nervous tissues range from 1.1 to 15.3 and from 0.7 to 4.5μmol/min per g fresh wt. respectively. Unfortunately the activities of these enzymes cannot be used to estimate maximal flux through the ketone-body-utilization pathway, since they may catalyse reactions that are close to equilibrium. Nonetheless, the presence of these enzymes in nervous tissue from a large variety of animals suggests that the importance of ketone bodies as a fuel for nervous tissue may be widespread in the animal kingdom.

scholarly journals Metabolic substrate utilization by tumour and host tissues in cancer cachexia

1991 ◽  
Vol 277 (2) ◽  
pp. 321-326 ◽  
Author(s):  
H D Mulligan ◽  
M J Tisdale
Keyword(s):  
Glucose Utilization ◽  
Ketone Bodies ◽  
Metabolic Demand ◽  
Fed State ◽  
Tumour Bearing ◽  
Coa Transferase ◽  
The Brain ◽  
Host Tissues

Utilization of metabolic substrates in tumour and host tissues was determined in the presence or absence of two colonic tumours, the MAC16, which is capable of inducing cachexia in recipient animals, and the MAC13, which is of the same histological type, but without the effect on host body composition. Glucose utilization by different tissues was determined in vivo by the 2-deoxyglucose tracer technique. Glucose utilization by the MAC13 tumour was significantly higher than by the MAC16 tumour, and in animals bearing tumours of either type the tumour was the second major consumer of glucose after the brain. This extra demand for glucose was accompanied by a marked decrease in glucose utilization by the epididymal fat-pads, testes, colon, spleen, kidney and, in particular, the brain, in tumour-bearing animals irrespective of cachexia. The decrease in glucose consumption by the brain was at least as high as the metabolic demand by the tumour. This suggests that the tissues of tumour-bearing animals adapt to use substrates other than glucose and that alterations in glucose utilization are not responsible for the cachexia. Studies in vitro showed that brain metabolism in the tumour-bearing state was maintained by an increased use of lactate and 3-hydroxybutyrate, accompanied by a 50% increase in 3-oxoacid CoA-transferase. This was supported by studies in vivo which showed an increased metabolism of 3-hydroxybutyrate in tumour-bearing animals. Thus ketone bodies may be utilized as a metabolic fuel during the cancer-bearing state, even though the nutritional conditions mimic the fed state.

Metabolic Seizure Resistance via BAD and KATP Channels

2016 ◽  
Author(s):  
Juan Ramón Martínez-François ◽  
Nika N. Danial ◽  
Gary Yellen
Keyword(s):  
Glucose Metabolism ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Katp Channels ◽  
Anticonvulsant Effect ◽  
Metabolic Function ◽  
Genetic Ablation ◽  
Electrographic Seizures ◽  
The Brain

On a ketogenic diet, ketone bodies provide an alternative fuel, replacing much of the glucose used ordinarily by the brain. This switch is thought to underlie its anticonvulsant effects. Brain fuel utilization can also be modified by a nondietary approach: genetic alteration of the protein BAD, which has known roles in regulating both apoptosis and glucose metabolism. When the metabolic function of BAD is genetically altered in mice, it produces reduced glucose and increased ketone body metabolism in neurons and astrocytes. This effect is related to regulation of BAD by phosphorylation and is independent of its apoptotic function. Mice with BAD modifications that produce decreased glucose metabolism exhibit a marked increase in the activity of neuronal ATP-sensitive potassium (KATP) channels and strong resistance to behavioral and electrographic seizures in vivo. This seizure resistance is lost upon genetic ablation of KATP channels, suggesting that KATP channels mediate BAD’s anticonvulsant effect.

scholarly journals Ketone-body utilization by adult and suckling rat brain in vivo

1971 ◽  
Vol 122 (1) ◽  
pp. 13-18 ◽  
Author(s):  
R. A. Hawkins ◽  
D. H. Williamson ◽  
H. A. Krebs
Keyword(s):  
Rat Brain ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Venous Blood ◽  
Adult Rats ◽  
Suckling Rats ◽  
Arterial Blood ◽  
The Brain ◽  
Body Concentration

1. Ketone-body utilization in fed and starved adult and suckling rats has been investigated by measuring arterio-venous differences across the brain. Venous blood was collected from the confluence of sinuses and arterial blood from the femoral artery in adult rats and by cardiac puncture in suckling rats. 2. During starvation the arterio-venous difference of ketone bodies increased in proportion to their concentrations in the blood and reached a value of 0.16mm at 48h. At a given concentration of the respective ketone bodies the arterio-venous differences of acetoacetate were about twice those of 3-hydroxybutyrate. 3. Fed rats in which the concentrations of ketone bodies were raised by intravenous infusion of sodium acetoacetate had the same arterio-venous differences as starved rats at corresponding ketone-body concentrations. Thus the ability of the rat brain to utilize ketone bodies is independent of the nutritional state. 4. The concentrations of glucose, acetoacetate and 3-hydroxybutyrate were much lower in the brain than in the arterial blood. The measured (blood concentration)/(brain concentration) ratio was 4.4 for glucose, 4.5 for acetoacetate and 8.1 for 3-hydroxybutyrate in 48h-starved rats. 5. The mean arterio-venous difference of glucose across the brain was 0.51mm in fed rats and 0.43mm in 96h-starved rats. 6. Conversion of glucose into lactate rose from negligible values in the fed state to 0.2mm after 48h starvation and decreased to zero after 96h starvation. 7. In 16–22-day-old suckling rats the arterio-venous differences of ketone bodies across the brain were also proportional to the ketone-body concentration, but they were about 3–4 times greater than in adult rats at the same blood ketone-body concentration. 8. Arterio-venous differences of glucose were about the same in adult and suckling rats. 9. The brain of fed suckling rats formed more lactate from glucose than fed adult rats. 10. The results indicate that ketone bodies are major metabolic fuels of the brain of the suckling rat under normal conditions.

Model of the kinetics of ketone bodies in humans

1982 ◽  
Vol 243 (1) ◽  
pp. R7-R17 ◽  
Author(s):  
C. Cobelli ◽  
R. Nosadini ◽  
G. Toffolo ◽  
A. McCulloch ◽  
A. Avogaro ◽  
...  
Keyword(s):  
Ketone Body ◽  
Specific Activity ◽  
Ketone Bodies ◽  
Mathematical Representation ◽  
Parameter Estimates ◽  
Extrahepatic Tissues ◽  
Body Compartments ◽  
Body Production ◽  
Kinetics Of

The kinetics of ketone bodies was studied in normal humans by giving a combined bolus intravenous injection of labeled acetoacetate ([14C]AcAc) and D(--)-beta-hydroxybutyrate (beta-[14C]-OHB) to seven subjects after an overnight fast, on two different occasions, and by collecting frequent blood samples for 100 min. Kinetic data were analyzed with both noncompartmental and compartmental modeling techniques. A four-compartment model, representing AcAc and beta-OHB in blood and two equilibrating ketone body compartments, inside the liver and extrahepatic tissues, was chosen as the most reliable mathematical representation; it is physiologically plausible and was able to accurately fit the data. The model permitted evaluation of the in vivo rate of ketone body production in the liver, the individual plasma clearance rates of AcAc and beta-OHB, their initial volumes of distribution, and the transfer rate parameters among the four ketone body compartments. Moreover, the model provided estimates of the components of the rates of appearance of AcAc and beta-OHB in plasma due to newly synthesized ketone body from acetyl-CoA in the liver, and to interconversion and recycling in the liver and extrahepatic tissues. The model also was used to evaluate other methodologies currently employed in the analysis of ketone body turnover data: the conventional approach based on use of the combined specific activity of AcAc and beta-OHB required assumptions not satisfied in vivo, leading to substantial errors in key parameter estimates.

Diabetes-associated nitration of tyrosine and inactivation of succinyl-CoA:3-oxoacid CoA-transferase

2001 ◽  
Vol 281 (6) ◽  
pp. H2289-H2294 ◽  
Author(s):  
Illarion V. Turko ◽  
Sisi Marcondes ◽  
Ferid Murad
Keyword(s):  
Catalytic Activity ◽  
Matrix Protein ◽  
Ketone Bodies ◽  
Tyrosine Nitration ◽  
Alternative Source ◽  
In Vivo Models ◽  
Protein Tyrosine ◽  
Protein Tyrosine Nitration ◽  
Coa Transferase

High levels of reactive species of nitrogen and oxygen in diabetes may cause modifications of proteins. Recently, an increase in protein tyrosine nitration was found in several diabetic tissues. To understand whether protein tyrosine nitration is the cause or the result of the associated diabetic complications, it is essential to identify specific proteins vulnerable to nitration with in vivo models of diabetes. In the present study, we have demonstrated that succinyl-CoA:3-oxoacid CoA-transferase (SCOT; EC 2.8.3.5 ) is susceptible to tyrosine nitration in hearts from streptozotocin-treated rats. After 4 and 8 wk of streptozotocin administration and diabetes progression, SCOT from rat hearts had a 24% and 39% decrease in catalytic activity, respectively. The decrease in SCOT catalytic activity is accompanied by an accumulation of nitrotyrosine in SCOT protein. SCOT is a mitochondrial matrix protein responsible for ketone body utilization. Ketone bodies provide an alternative source of energy during periods of glucose deficiency. Because diabetes results in profound derangements in myocardial substrate utilization, we suggest that SCOT tyrosine nitration is a contributing factor to this impairment in the diabetic heart.

P3476High-resolution respirometry reveals enhanced myocardial mitochondrial ketone oxidation after fasting and ventricular unloading

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
E Zweck ◽  
V Burkart ◽  
C Wessel ◽  
D Scheiber ◽  
K H M Leung ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Ex Vivo ◽  
Oxidative Capacity ◽  
Left Ventricular ◽  
University Hospital ◽  
Oxygen Flux ◽  
Protective Effects ◽  
Coa Transferase

Abstract Background Impairment of myocardial mitochondrial function is regarded as an established pathomechanism in heart failure. Enhanced oxidation of ketone bodies may potentially exert protective effects on myocardial function. High-resolution respirometry (HRR) resembles a gold-standard methodology to determine myocardial mitochondrial metabolism and oxidative function but has not been validated for ketone substrates yet. Purpose We hypothesized that (1) quantification of ketone body oxidative capacity (OC) in myocardium utilizing ex-vivo HRR is feasible and that (2) ketone-associated OC is elevated after fasting and under conditions of chronic mechanical ventricular unloading. Methods We established new HRR (Oxygraph-2k) protocols, measuring oxygen flux generated by oxidation of the ketone substrates beta-hydroxybutyrate (HBA) and acetoacetate (ACA). Ketone protocols were then applied to twelve C57BL/6 mice' (of which six were fasted for 16h) left ventricular and right liver lobe tissue, as well as to eleven terminal heart failure patients' left ventricular tissue, harvested at heart transplantation. Heart transplant recipients were subdivided into patients with left ventricular assist device prior to transplantation (LVAD group, n=6) or no unloading prior to transplantation (HTX group, n=5). Results In non-fasted rodent hearts, HBA yielded an OC of 25±4 pmol/(s*mg tissue) above basal respiration, when applied as sole substrate (21±11 pmol/(s*mg) in liver). ACA alone did not induce oxygen flux, but ACA+succinate yielded 229% higher oxygen flux than succinate alone in state III (146±32 vs 44±12 pmol/(s*mg); p=0.0003). When titrated after succinate, ACA increased OC by 93±25 pmol/(s*mg) (p=0.0003). In 16h-fasted rodent hearts, HBA-supported OC was 27% higher (41±3 vs 52±9 pmol/(s*mg); p=0.04), while OC with ACA+succinate was unchanged (p=0.60). In rodent liver, no oxygen flux was induced by ACA, reflecting absence of 3-oxoacid CoA-transferase. However, HBA-supported OC was 118% higher in fasted liver (37±13 vs 57±13 pmol/(s*mg); p=0.03). In humans, left ventricular unloading was not associated with altered myocardial OC for fatty acids and glycolytic substrates (standard protocol, p=0.13), but HBA-supported OC was 39% higher in the LVAD group compared to the HTX group (54±12 vs 39±9 pmol/(s*mg), p=0.04). Conclusion Quantification of ketone body OC with HRR is feasible in permeabilized myocardial fibers. Applying this novel method revealed increased HBA-supported myocardial mitochondrial respiration after fasting and chronic left ventricular unloading. These data support a concept of enhanced ketone oxidation following ventricular unloading in myocardial mitochondria. Our findings facilitate new studies on myocardial ketone turnover and the interaction of mitochondrial ketone metabolism with cardiac performance. Acknowledgement/Funding CRC 1116, Research commission of the University Hospital Düsseldorf

Fetal glucose utilization in response to maternal starvation and acute hyperketonemia

1989 ◽  
Vol 256 (6) ◽  
pp. E699-E703 ◽  
Author(s):  
A. Leturque ◽  
S. Hauguel ◽  
J. P. Revelli ◽  
A. F. Burnol ◽  
J. Kande ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Ketone Body ◽  
Glucose Utilization ◽  
Fetal Liver ◽  
Rat Tissues ◽  
Pregnant Rats ◽  
Hindlimb Muscles ◽  
Decrease Blood Glucose ◽  
Beta Hydroxybutyrate

The effects of maternal hypoglycemia and/or hyperketonemia on glucose utilization by individual fetal rat tissues have been studied in vivo. To decrease blood glucose and to raise fetal blood ketone body concentrations, 19-day pregnant rats were submitted to 48 or 96 h of starvation. To differentiate between the effects of decreased blood glucose and increased ketone body concentrations, fed pregnant rats were infused for 2 h with DL-beta-hydroxybutyrate. After 96 h of maternal starvation, fetal 2-deoxy-D-glucose (2DG) uptake decreased from 13.6 +/- 0.5 to 8.6 +/- 1.15 micrograms.min-1.g-1. This was mainly due to a decrease in 2DG uptake by fetal hindlimb muscles and heart. By contrast, 2DG uptake in fetal liver and brain was not affected by maternal starvation. Acute hyperketonemia in fed pregnant rats induced a 23% decrease in 2DG uptake by the whole fetus mainly as the result of a lowered 2DG uptake in fetal hindlimb muscles. These data suggest that fetal 2DG uptake does not simply depend on lowered blood glucose level during maternal starvation but that other hormonal, cardiovascular, or metabolic adaptations are implicated. In the rat, most of the fetal tissues including brain are protected against maternal hypoglycemia.

The transport of ketone bodies into the brain of the rat (in vivo)

1977 ◽  
Vol 34 (1) ◽  
pp. 1-13 ◽  
Author(s):  
P.M. Daniel ◽  
E.R. Love ◽  
S.R. Moorhouse ◽  
O.E. Pratt
Keyword(s):  
Ketone Bodies ◽  
The Brain

scholarly journals Regulation of glucose and ketone-body metabolism in brain of anaesthetized rats

1974 ◽  
Vol 138 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Neil B. Ruderman ◽  
Peter S. Ross ◽  
Michael Berger ◽  
Michael N. Goodman
Keyword(s):  
Glucose Uptake ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Acetyl Coa ◽  
Total Blood ◽  
Diabetic Ketosis ◽  
Pyruvate Oxidation ◽  
Ketone Body Metabolism ◽  
Arteriovenous Difference ◽  
The Brain

1. The effects of starvation and diabetes on brain fuel metabolism were examined by measuring arteriovenous differences for glucose, lactate, acetoacetate and 3-hydroxybutyrate across the brains of anaesthetized fed, starved and diabetic rats. 2. In fed animals glucose represented the sole oxidative fuel of the brain. 3. After 48h of starvation, ketone-body concentrations were about 2mm and ketone-body uptake accounted for 25% of the calculated O2 consumption: the arteriovenous difference for glucose was not diminished, but lactate release was increased, suggesting inhibition of pyruvate oxidation. 4. In severe diabetic ketosis, induced by either streptozotocin or phlorrhizin (total blood ketone bodies >7mm), the uptake of ketone bodies was further increased and accounted for 45% of the brain 's oxidative metabolism, and the arteriovenous difference for glucose was decreased by one-third. The arteriovenous difference for lactate was increased significantly in the phlorrhizin-treated rats. 5. Infusion of 3-hydroxybutyrate into starved rats caused marked increases in the arteriovenous differences for lactate and both ketone bodies. 6. To study the mechanisms of these changes, steady-state concentrations of intermediates and co-factors of the glycolytic pathway were determined in freeze-blown brain. 7. Starved rats had increased concentrations of acetyl-CoA. 8. Rats with diabetic ketosis had increased concentrations of fructose 6-phosphate and decreased concentrations of fructose 1,6-diphosphate, indicating an inhibition of phosphofructokinase. 9. The concentrations of acetyl-CoA, glycogen and citrate, a potent inhibitor of phosphofructokinase, were increased in the streptozotocin-treated rats. 10. The data suggest that cerebral glucose uptake is decreased in diabetic ketoacidosis owing to inhibition of phosphofructokinase as a result of the increase in brain citrate. 11. The inhibition of brain pyruvate oxidation in starvation and diabetes can be related to the accelerated rate of ketone-body metabolism; however, we found no correlation between the decrease in glucose uptake in the diabetic state and the arteriovenous difference for ketone bodies. 12. The data also suggest that the rates of acetoacetate and 3-hydroxybutyrate utilization by brain are governed by their concentrations in plasma. 13. The finding of very low concentrations of acetoacetate and 3-hydroxybutyrate in brain compared with plasma suggests that diffusion across the blood –brain barrier may be the rate-limiting step in their metabolism.

Pseudoketogenesis in hepatectomized dogs

1990 ◽  
Vol 258 (3) ◽  
pp. E519-E528 ◽  
Author(s):  
C. Des Rosiers ◽  
J. A. Montgomery ◽  
M. Garneau ◽  
F. David ◽  
O. A. Mamer ◽  
...  
Keyword(s):  
Bolus Injection ◽  
Specific Activity ◽  
Ketone Bodies ◽  
Gas Chromatography Mass Spectrometry ◽  
Selected Ion Monitoring ◽  
Coa Transferase ◽  
Net Uptake ◽  
Extrahepatic Tissues ◽  
Molar Percent

Overestimation of ketone body turnover in vivo, measured by tracer kinetics, could occur if specific activity or molar percent enrichment is diluted in extrahepatic tissues by label exchange via reversal of 3-oxoacid-CoA transferase, a process we call pseudoketogenesis. To test this hypothesis, euglycemic hepatectomized dogs were injected with a bolus of acetoacetate (0.8 mmol/kg), 32% enriched in [3,4-13C2]acetoacetate. Concentrations and labeling patterns of blood acetoacetate and R-3-hydroxybutyrate were measured by selected ion-monitoring gas chromatography-mass spectrometry. During the 60 min after bolus injection of [3,4-13C2]acetoacetate, the molar percent enrichment of blood [3,4-13C2]acetoacetate decreased to 73 +/- 3% (n = 5) in controls and to 11.5 +/- 0.8% (n = 3) during infusion of dichloroacetate, an activator of pyruvate dehydrogenase. The enrichment of R-3-hydroxy-[3,4-13C2]butyrate followed closely that of [3,4-13C2]acetoacetate. These dilutions occurred despite a net uptake of ketone bodies. Concomitantly, 10.6 +/- 2.2 (n = 5) and 6.0 +/- 2.9% (n = 3) of [13C]acetoacetate molecules were labeled on all four carbons in control and dichloroacetate-treated dogs, respectively. This uniformly labeled acetoacetate arises from partial equilibration between [3,4-13C2]acetoacetate and [1,2-13C2]acetyl-CoA via the reactions catalyzed by 3-oxoacid-CoA transferase and acetoacetyl-CoA thiolase. Our data demonstrate the reversibility of the 3-oxoacid-CoA transferase in intact extrahepatic tissues and support the concept of pseudoketogenesis. This phenomenon has been quantitated by kinetic analysis of the data.

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