scholarly journals The course of ketosis and the activity of key enzymes of ketogenesis and ketone-body utilization during development of the postnatal rat

1971 ◽  
Vol 124 (1) ◽  
pp. 249-254 ◽  
Author(s):  
Elizabeth A. Lockwood ◽  
E. Bailey
Keyword(s):  
Specific Activity ◽  
Ketone Bodies ◽  
Mitochondrial Enzyme ◽  
Suckling Period ◽  
Stages Of Development ◽  
Development Activity ◽  
Blood Concentrations ◽  
Time Activity ◽  
Developmental Patterns ◽  
Coa Transferase

1. The highest blood concentrations of ketone bodies were found at 5 days of age, after which time the concentration fell to reach the adult value by 30 days of age. 2. Both mitochondrial and cytoplasmic hydroxymethylglutaryl-CoA synthase activities were detected, with highest activities being found in the mitochondria at all stages of development. Activity of the mitochondrial enzyme increases rapidly immediately after birth, showing a maximum at 15 days of age, thereafter falling to adult values. The cytoplasmic enzyme, on the other hand, increased steadily in activity after birth to reach a maximum at 40 days of age, after which time activity fell to adult values. 3. Both mitochondrial and cytoplasmic aceto-acetyl-CoA thiolase activities were detected, with the mitochondrial enzyme having considerably higher activities at all stages of development. The developmental patterns for both enzymes were very similar to those for the corresponding hydroxymethylglutaryl-CoA synthases. 4. The activity of heart acetoacetyl-CoA transferase remains constant from late foetal life until the end of the suckling period, after which time there is a gradual threefold increase in activity to reach the adult values. The activity of brain 3-oxo acid CoA-transferase increases steadily after birth, reaching a maximum at 30 days of age, thereafter decreasing to adult values, which are similar to foetal activities. Although at all stages of development the specific activity of the heart enzyme is higher than that of brain, the total enzymic capacity of the brain is higher than that of the heart during the suckling period.

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.

scholarly journals Activities of enzymes of ketone-body utilization in brain and other tissues of suckling rats

1971 ◽  
Vol 121 (1) ◽  
pp. 49-53 ◽  
Author(s):  
M. Ann Page ◽  
H. A. Krebs ◽  
D. H. Williamson
Keyword(s):  
Rat Brain ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Rat Kidney ◽  
Adult Brain ◽  
Suckling Period ◽  
Suckling Rats ◽  
Adult Rat ◽  
Coa Transferase ◽  
High Concentrations

1. The activities of 3-hydroxybutyrate dehydrogenase and 3-oxo acid CoA-transferase in rat brain at birth were found to be about two-thirds of those of adult rat brain, expressed per g wet wt. The activities rose throughout the suckling period and at the time of weaning reached values about three times higher than those for adult brain. Later they gradually declined. 2. At birth the activity of acetoacetyl-CoA thiolase in rat brain was about 60% higher than in the adult. During the suckling period there was no significant change in activity. 3. In rat kidney the activities of the three enzymes at birth were less than one-third of those at maturity. They gradually rose and after 5 weeks approached the adult value. Similar results were obtained with rat heart. 4. The activity of glutamate dehydrogenase (a mitochondrial enzyme like 3-hydroxybutyrate dehydrogenase and 3-oxo acid CoA-transferase) also rose in brain and kidney during the suckling period, but at no stage did it exceed the adult value. 5. Throughout the suckling period the total ketone-body concentration in the blood was about six times higher than in adult fed rats, and the concentration of free fatty acids in the blood was three to four times higher. 6. It is concluded that the rate of ketone-body utilization in brains of suckling rats is determined by both the greater amounts of the key enzymes in the tissue and the high concentrations of ketone bodies in the blood. In addition, the low activities of the relevant enzymes in kidney and heart of suckling rats may make available more ketone bodies for the brain.

scholarly journals Activities of enzymes of fat and ketone-body metabolism and effects of starvation on blood concentrations of glucose and fat fuels in teleost and elasmobranch fish

1979 ◽  
Vol 184 (2) ◽  
pp. 313-322 ◽  
Author(s):  
Victor A. Zammit ◽  
Eric A. Newsholme
Keyword(s):  
Fatty Acids ◽  
Ketone Body ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Ketone Bodies ◽  
Carnitine Palmitoyltransferase ◽  
Blood Metabolites ◽  
Activity Data ◽  
Blood Concentrations ◽  
Esterified Fatty Acids ◽  
Coa Transferase

1. Activities of 3-oxo acid CoA-transferase and carnitine palmitoyltransferase together with tri- and di-acylglycerol lipase were present in red and heart muscles of the teleost fish. However, d-3-hydroxybutyrate dehydrogenase activity was not detectable. These results suggest that the heart and red muscles of the teleosts should be able to utilize the fat fuels triacylglycerol, fatty acids or acetoacetate, but not hydroxybutyrate. The muscles from the elasmobranchs differed in that d-3-hydroxybutyrate dehydrogenase and 3-oxo acid CoA-transferase activities were present, but carnitine palmitoyltransferase activity was not detectable. This suggests that ketone bodies are the most important fat fuels in elasmobranchs. 2. The concentrations of acetoacetate, 3-hydroxybutyrate, glycerol, non-esterified fatty acids and triacylglycerols were measured in blood or plasma of several species of fish (teleosts and elasmobranchs) in the fed state. Teleosts have a 10-fold higher concentration of plasma non-esterified fatty acids, but a lower blood concentration of ketone bodies; both acetoacetate and 3-hydroxybutyrate are present in blood of elasmobranchs, whereas 3-hydroxybutyrate is absent from that of the teleosts. 3. The effects of starvation (up to 150 days) on the concentrations of blood metabolites were studied in a teleost (bass) and an elasmobranch (dogfish). In the bass there was a 60% decrease in blood glucose after 100 and 150 days starvation. In dogfish there was a large increase in the concentration of ketone bodies, whereas in bass the concentration of acetoacetate (the only ketone body present) remained low (<0.04mm) throughout the period of starvation. The concentration of plasma non-esterified fatty acids increased in bass, but decreased in dogfish. These changes are consistent with the predictions based on the enzyme-activity data. 4. Starvation did not change the activities of ketone-body-utilizing enzymes or that of phosphoenolpyruvate carboxykinase in heart and red skeletal muscles of both fish, but it decreased markedly the activity of phosphoenolpyruvate carboxykinase in white skeletal muscle of both fish. However, in the liver of the dogfish, starvation resulted in a twofold increase in the activities of 3-hydroxybutyrate dehydrogenase and acetoacetyl-CoA thiolase, whereas in bass liver it decreased the activity of acetoacetyl-CoA thiolase and increased that of 3-oxo acid CoA-transferase. The activity of phosphoenolpyruvate carboxykinase was increased twofold in the liver of bass, but was unchanged in that of the dogfish. 5. The difference in changes in concentrations of blood metabolites and enzyme activities in the two fish support the suggestion that, in starvation, ketone bodies, but not non-esterified fatty acids, are an important fuel for muscle in elasmobranchs, whereas non-esterified fatty acids, but not ketone bodies, are an important fuel in teleosts. The results are discussed in relation to the evolution of a discrete lipid-storing adipose tissue in teleosts and higher vertebrates.

Studies on the carbohydrate metabolism of sheep. XVI. Partition of ketone bodies in blood, tissues, and urine

1962 ◽  
Vol 13 (2) ◽  
pp. 307 ◽  
Author(s):  
RL Reid
Keyword(s):  
Renal Clearance ◽  
Blood Level ◽  
Ketone Bodies ◽  
Urine Flow ◽  
Blood Levels ◽  
Renal Tubules ◽  
Hydroxybutyric Acid ◽  
Acetoacetic Acid ◽  
Tissue Concentrations ◽  
Blood Concentrations

Acetone comprised 0–40% (average 18%) of the acetoacetic acid plus acetone fraction in sheep blood, in which the level of this fraction was 0.6–5.2 mg % (as acetone). Acetoacetic acid was largely converted to acetone during storage of blood at –20°C, with intermittent thawing for analysis. Concentrations of acetoacetic acid in red cells were similar to those in plasma, but those of ß-hydroxybutyric acid were considerably lower. In contrast to acetoacetic acid, ß-hydroxybutyric acid was virtually absent from foetal blood and from brain tissue. Concentrations of both ketone fractions in liver and muscle tissue were about one-half the blood concentrations. The renal clearance of acetoacetic acid plus acetone in hyperketonaemic pregnant ewes was independent of blood level up to 20 mg % and was little affected by rate of urine flow. Clearance values were in the range of 4–9 ml per min, which indicates that most of the acetoacetic acid filtered at the glomeruli is absorbed by the renal tubules. Renal clearance of ß-hydroxybutyric acid was dependent on blood level and was more affected by rate of urine flow than that of acetoacetic acid. Very little ß-hydroxybutyric acid appeared in the urine when blood levels were below 15 mg %. Clearance increased as blood concentration rose above this level, and reached maximum values, mostly of 3–5 ml per min, at blood levels exceeding 30 mg %.

scholarly journals Gluconeogenesis in the cow. The effects of a glucocorticoid on hepatic intermediary metabolism

1970 ◽  
Vol 116 (5) ◽  
pp. 865-874 ◽  
Author(s):  
G. D. Baird ◽  
R. J. Heitzman
Keyword(s):  
Blood Glucose ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Tyrosine Aminotransferase ◽  
Aspartate Transaminase ◽  
Blood Concentrations ◽  
Lactating Cows ◽  
Glycolytic Intermediates ◽  
Blood Glucose Concentrations ◽  
Parallel Measurements

1. The hepatic concentrations of the ketone bodies and of metabolites and activities of enzymes involved in gluconeogenesis were measured in healthy lactating and non-lactating cows 48h after administration of Voren, an ester of dexamethasone, and compared with those found in control animals given saline. Parallel measurements were also made of the blood concentrations of several of the metabolites. 2. Blood glucose concentrations were raised in the Voren-treated animals, whereas blood ketone body and free fatty acid concentrations were unaltered. Similarly there was no change in the hepatic concentrations of the ketone bodies. 3. Significant increases were found in the hepatic concentrations of citrate, 2-oxo-glutarate and malate in both groups of animals given Voren. 4. The hepatic concentrations of those glycolytic intermediates that were measured either decreased or did not change after Voren treatment. 5. The enzymes aspartate transaminase and fructose 1,6-diphosphatase were unchanged in activity after Voren administration, whereas phosphopyruvate carboxylase (EC 4.1.1.32) activity was depressed in the lactating group. However, glucose 6-phosphatase, tryptophan oxygenase and tyrosine aminotransferase increased in activity. 6. In several cases those hepatic metabolites that increased in concentration after Voren administration were present in lower concentration in normal lactating cows than in normal non-lactating cows. The same applied mutatis mutandis to those metabolites that were decreased by Voren. 7. These findings are discussed in relation to the use of glucocorticoids in the treatment of bovine ketosis.

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.

New insights into lactase and glycosylceramidase activities of rat lactase-phlorizin hydrolase

1989 ◽  
Vol 257 (4) ◽  
pp. G616-G623 ◽  
Author(s):  
H. A. Buller ◽  
A. G. Van Wassenaer ◽  
S. Raghavan ◽  
R. K. Montgomery ◽  
M. A. Sybicki ◽  
...  
Keyword(s):  
Active Sites ◽  
Specific Activity ◽  
Fold Increase ◽  
Developmental Pattern ◽  
Lactose Hydrolysis ◽  
Adult Males ◽  
Lactase Activity ◽  
Developmental Patterns ◽  
Catalytic Sites ◽  
Hydrolysis Of

Lactase-phlorizin hydrolase, a small intestinal disaccharidase, has been considered mainly an enzyme important only for the hydrolysis of lactose. After weaning in most mammals lactase-specific activity falls markedly, and, functionally, adult mammals are considered to be lactase deficient. However, the persistence of low levels of lactase activity in adulthood has never been explained. In addition, it has been suggested that lactase-phlorizin hydrolase is associated with glycosylceramidase activity when the enzyme is prepared by column chromatography, but it is unclear whether this represents copurified activities or two catalytic sites on one peptide. The developmental patterns of lactase-phlorizin hydrolase and other disaccharidases were investigated in homogenates of total rat small intestine; lactase and several glycosylceramidases were measured in immunoprecipitates from these homogenates using a monoclonal antibody. The developmental pattern of total lactase activity showed a steady 2.3-fold increase to adult levels (specific activity decreased eightfold), whereas total phlorizin-hydrolase activity increased 10.7-fold (specific activity decreased threefold). As expected, levels of both total and specific sucrase and maltase activities increased during development. In lactating rats total lactase activity showed a significant increase compared with adult males. The developmental pattern of the enzyme activities for the glycolipid substrates was similar to that found for lactase, and the immunoprecipitated enzyme showed a 40- to 55-fold higher affinity for the glycolipids than for lactose. Galactosyl- and lactosylceramide inhibited lactose hydrolysis by 38%, without a competitive pattern, suggesting two different active sites for lactose and glycolipid hydrolysis, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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

scholarly journals Effects of starvation on intermediary metabolism in the lactating cow. A comparison with metabolic changes occurring during bovine ketosis

1972 ◽  
Vol 128 (5) ◽  
pp. 1311-1318 ◽  
Author(s):  
G. D. Baird ◽  
R. J. Heitzman ◽  
K. G. Hibbitt
Keyword(s):  
Fatty Acids ◽  
Plasma Concentration ◽  
Dairy Cows ◽  
Blood Concentration ◽  
Ketone Bodies ◽  
Fat Metabolism ◽  
Metabolic Changes ◽  
Initial Increase ◽  
Blood Concentrations ◽  
Lactating Dairy Cows

1. The purpose of this study was to determine the nature of the metabolic changes associated with carbohydrate and fat metabolism that occurred in the blood and liver of lactating dairy cows during starvation for 6 days. 2. During starvation, the blood concentrations of the free fatty acids and ketone bodies increased, whereas that of citrate decreased. After an initial increase, the blood concentration of glucose subsequently declined as starvation progressed. Starvation caused a significant decrease in the plasma concentration of serine and a significant increase in that of leucine. 3. After 6 days of starvation the hepatic concentrations of oxaloacetate, citrate, phosphoenolpyruvate, 2-phosphoglycerate, 3-phosphoglycerate, glucose, glycogen, ATP and NAD+ had all decreased, as had the hepatic activities of phosphopyruvate carboxylase (EC 4.1.1.32) and pyruvate kinase (EC 2.7.1.40). 4. The above metabolic changes are similar to those previously found to occur in cows suffering from spontaneous ketosis (Baird et al., 1968; Baird & Heitzman, 1971). 5. Milk yield decreased progressively during starvation. 6. There were marked differences in the ability of individual animals to resist the onset of severe starvation ketosis.

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