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PubMed1976

Acetone production by methylobacteria.

An accumulation of acetone was observed during the metabolism of ethane and products of ethane oxidation by washed suspensions of Methylosinus trichosporium OB3B. This strain possessed an acetoacetate decarboxylase and 3-hydroxybutyrate dehydrogenase, and a decline in poly-beta-hydroxybutyric acid occurred under the same conditions as acetone formation. A pathway of acetone production from poly-beta-hydroxybutyric acid via 3-hydroxybutyrate and acetoacetate was suggested.

Acetoacetates↗
PubMed1982

Ketone-body utilization by homogenates of adult rat brain.

The regulation of ketone-body metabolism and the quantitative importance of ketone bodies as lipid precursors in adult rat brain has been studied in vitro. Utilization of ketone bodies and of pyruvate by homogenates of adult rat brain was measured and the distribution of 14C from [3-14C]ketone bodies among the metabolic products was analysed. The rate of ketone-body utilization was maximal in the presence of added Krebs-cycle intermediates and uncouplers of oxidative phosphorylation. The consumption of acetoacetate was faster than that of D-3-hydroxybutyrate, whereas, pyruvate produced twice as much acetyl-CoA as acetoacetate under optimal conditions. Millimolar concentrations of ATP in the presence of uncoupler lowered the consumption of ketone bodies but not of pyruvate. Indirect evidence is presented suggesting that ATP interferes specifically with the mitochondrial uptake of ketone bodies. Interconversion of ketone bodies and the accumulation of acid-soluble intermediates (mainly citrate and glutamate) accounted for the major part of ketone-body utilization, whereas only a small part was oxidized to CO2. Ketone bodies were not incorporated into lipids or protein. We conclude that adult rat-brain homogenates use ketone bodies exclusively for oxidative purposes.

2,4-Dinitrophenol↗
PubMed1975

Aspects of ketogenesis: control and mechanism of ketone-body formation in isolated rat-liver mitochondria.

The synthesis of ketone bodies by intact isolated rat-liver mitochondria has been studied at varying rates of acetyl-CoA production and of acetyl-CoA utilization in the Krebs cycle. Factors which enhanced the rate of acetyl-CoA production caused an increase in the fraction of acetyl-CoA which was incorporated into ketone bodies. On the other hand, it was found that factors which stimulated the formation of citrate lowered the relative rate of ketogenesis. It is concluded that acetyl-CoA is preferentially used for citrate synthesis, if the level of oxaloacetate in the mitochondrial matrix space is adequate. The intramitochondrial level of oxaloacetate, which is determined by the malate concentration and the ratio of NADH over NAD+, is the main factor controlling the rate of citrate synthesis. The ATP/ADP ratio per se does not affect the activity of citrate synthase in this in vitro system. Ketogenesis can be described as an overflow of acetyl-groups: Ketone-body formation is stimulated only when the rate of acetyl-CoA production increases beyond the capacity for citrate synthesis. The interaction between fatty acid oxidation and pyruvate metabolism and the effects of long-chain acyl-CoA on mitochondrial metabolism are discussed. Ketone bodies which were generated during the oxidation of [1-14C] fatty acids were preferentially labelled in their carboxyl group. This carboxyl group had the same specific activity as the acetyl-CoA pool, whereas the specific activity of the acetone moiety of acetoacetate was much lower, especially at low rates of ketone-body formation. The activities of acetoacetyl-CoA deacylase and the hydroxymethylglutaryl-CoA (HMG-CoA) pathway were compared in soluble and mitochondrial fractions of rat- and cow-liver in different ketotic states. In rat-liver mitochondria, both pathways of acetoacetate synthesis were stimulated upon starvation or in alloxan diabetes. In cow liver, only the HMG-CoA pathway was increased during ketosis in the mitochondrial as well as in the soluble fraction.

Acetates↗
PubMed1988

D-3-hydroxybutyrate metabolism in the perfused rat heart.

The utilization of D-3-HB and the production of acetoacetate by the perfused rat heart were investigated over a wide range of DL-3-HB concentrations. The rate of D-3-HB utilization is concentration dependent, and shows saturation kinetics. The oxidized amount of D-3-HB when D-3-HB as a sole substrate, accounts at a maximum for 50% of the total oxygen consumption, which suggest the contribution of the endogenous substrate as fuel source along with D-3-HB. The proportion of the D-3-HB consumed that is oxidized rather than released as acetoacetate increases from 70% to 93% as the concentration of D-3-HB falls from 6.99 mM to 0.30 mM.

3-Hydroxybutyric Acid↗
PubMed1977

Relative utilization of fatty acids for synthesis of ketone bodies and complex lipids in the liver of developing rats.

The regulation of hepatic ketogenesis, as related to the metabolism of fatty acids through oxidative and synthetic pathways, was studied in developing rats. [1-14C] palmitate was used as a substrate to determine the proportions of free fatty acids utilized for the production of ketone bodies, CO2 and complex lipids. Similar developmental patterns of hepatic ketogenesis were obtained by measuring the production of either [14C] acetoacetate from exogenous [1-14C] palmitate or the sum of unlabeled acetoacetate and beta-hydroxybutyrate from endogenous fatty acids. The production of total ketone bodies was low during the late fetal stage and at birth, but increased rapidly to a miximum value within 24 hr after brith. The maximal ketogenic capacity appeared to be maintained for the first 10 days of life. 14CO2 production from [1-14C] palmitate increased by two- to fourfold during the suckling period, from its initial low rate seen at birth. The capacity for synthesis of total complex lipids was low at birth and had increased by day 3 to a maximal value, which was comparable to that of adult fed rats. The high lipogenic capacity lasted throughout the remaining suckling period. When ketogenesis was inhibited by 4-pentenoic acid, the rate of synthesis of complex lipids did not increase despite an increase in unutilized fatty acids. During the mid-suckling period, approximately equal amounts of [1-14C] palmitate were utilized for the synthesis of ketone plus CO2 and for complex lipid synthesis. By contrast, in adult fed rats, the incorporation of fatty acids into complex lipids was four times higher than that of ketone plus CO2. These observations suggest that stimulated hepatic ketogenesis in suckling rats results from the rapid oxidation of fatty acids and consequent increased production of acetyl CoA, but not from impaired capacity for synthesis of complex lipids.

Acetoacetates↗
PubMed1981

Fatty acid and cholesterol synthesis from specifically labeled leucine by isolated rat hepatocytes.

Hepatocytes isolated from female rats meal-fed a high-glucose diet were incubated in Krebs-Henseleit bicarbonate medium containing 16.5 mM glucose, 3H2O, and 14C-labeled amino acids (-)-Hydroxycitrate depressed the incorporation of 3H2O and [14C] alanine into fatty acids and cholesterol. Incorporation of [U-14C]leucine into lipids was not affected but incorporation of 3H2O into lipids was decreased significantly by (-)-hydroxycitrate. (-)-Hydroxycitrate depressed the incorporation of radioactivity from [2-14C]leucine into fatty acids and cholesterol by 61 and 38%, respectively, and stimulated the incorporation of radioactivity from [4,5-3H]leucine 35 and 28%. As [2-14C]leucine labels the acetyl-CoA pool and [4,5-3H]leucine labels the acetoacetate pool, it was concluded that mitochondrial 3-hydroxy-3-methylglutaryl-CoA is not incorporated intact into cholesterol, and that acetoacetate can be activated effectively in the liver cytosol for support of cholesterol and fatty acid synthesis.

Acetoacetates↗
PubMed1998

Markers of cellular dysoxia during orthotopic liver transplantation in pigs.

OBJECTIVE: To characterize global, regional, and end-organ markers of cellular dysoxia during orthotopic liver transplantation and early reperfusion in pigs. DESIGN: Descriptive study. SETTING: University hospital research laboratory. ANIMALS AND INTERVENTIONS: 7 fasted, anesthetized, and mechanically ventilated Yorkshire pigs underwent orthotopic liver transplantation. Oxygen consumption (VO2) and oxygen delivery (DO2) were both calculated using standard formulae. Gastric interstitial pH and the gastroarterial partial pressure of carbon dioxide (PCO2) gradient were measured with a gastric tonometer. The following were determined from arterial blood samples: serum lactate to pyruvate ratio, serum 3-hydroxybutyrate to acetoacetate ratio, plasma free fatty acids, and plasma free and total carnitine levels. MEASUREMENTS AND RESULTS: Data were collected 1 h after induction of anesthesia (I), at the end of the anhepatic phase (A), and 1 h after reperfusion (R), Median (range) VO2 values obtained at the specified time points were: I 318 (206-1860), A 210 (152-408), R 330 (214-424) ml/kg per min, respectively (NS); DO2 values were: I 1828 (1382-3259), A 1219 (452-2492), R 1741 (1345-12,071) ml/kg per min, respectively (NS). The lactate to pyruvate ratio, reflecting the redox potential of the cytosol, progressively increased: I 22 (9-46), A 29 (16-68), R 43 (23-55), (p < 0.05). Gastric interstitial pH, as well as the gastroarterial PCO2 gradient values at the specified time points did not reach statistical significance. Levels of ketone bodies (3-hydroxybutyrate+acetoacetate) remained lower than 0.120 mmol/l. The ketone body ratio did not significantly vary over time (NS). Plasma esterified and free carnitine concentrations and free fatty acid values remained within normal limits (NS). Among these markers, the ketone body ratio presented the largest area under the receiver operating characteristic curve as a marker of postoperative mortality, with an inflexion point at 0.9. CONCLUSION: In this study, orthotopic liver transplantation was associated with significant variations over time in the redox potential of the cytosol. Postoperative mortality was, however, related to the redox state of the liver mitochondria. Our data suggest the occurrence of abnormal tissue oxygenation during liver transplantation.

3-Hydroxybutyric Acid↗
PubMed2001

The determination of ketone bodies: preanalytical, analytical and physiological considerations.

The arterial ketone body ratio is calculated as the ratio of arterial levels of acetoacetate/beta-hydroxybutyrate. It correlates with survival in experimental hemorrhagic shock and outcome after liver surgery and myocardial infarction. Procedures for determination of ketone bodies are often laborious and unreliable. As yet the relationship between results from arterial and venous samples is unclear. We therefore describe the determination of the ketone bodies acetoacetate and 3-hydroxybutyrate by an easy, reliable, rapid, inexpensive enzymatic assay using 3-hydroxybutyrate dehydrogenase (E.C. 1.1.1.30) in a semi-automated setting that does not require deproteinization. Preanalytical parameters, including separation from corpuscular elements within 1 h and storage on ice for less than 1 h, must be strictly observed to avoid rapid decay of acetoacetate by spontaneous decarboxylation. The assay has high sensitivity, specificity (+/-5%), and precision (CV <2.5%) with a measurable range of 5-500 micromol/l for either ketone body, and requires only 23.5 microl of plasma. At temperatures below -17 degrees C plasma may be stored for prolonged periods. Results from prospectively scheduled simultaneous sampling of arterial blood and venous blood from the right atrium in 100 consecutive patients with severe multiple trauma (mean Injury Severity Score 38+/-13) support the view that the lung has no role in ketone body metabolism. We conclude that central venous blood can safely be substituted for arterial blood for determination of the ketone body ratio.

3-Hydroxybutyric Acid↗
PubMed1983

A spectrophotometric, enzymatic assay for D-3-hydroxybutyrate that is not dependent on hydrazine.

Because of the potential carcinogenic properties of hydrazine and because of other health hazards associated with its use in the laboratory, an enzymatic assay has been developed for D-3-hydroxybutyrate that is not dependent on hydrazine to drive the reaction toward completion. The use of a high concentration of NAD+ and a buffer at pH 9.5 resulted in a favorable conversion of D-3-hydroxybutyrate to acetoacetate by D-3-hydroxybutyrate dehydrogenase even though the reaction favors D-3-hydroxybutyrate formation under physiological conditions. The assay was also completed faster than previous assays using hydrazine so that the amount of enzyme used for the assay could be reduced. The recovery of D-3-hydroxybutyrate added to liver samples was 98 +/- 1% (mean +/- SEM, n = 6). The assay was found to be suitable for the measurement of D-3-hydroxybutyrate in samples such as perchloric acid extracts of isolated hepatocytes even when the acetoacetate to D-3-hydroxybutyrate ratio was 4 to 1. This assay presents a reliable alternative to the use of hydrazine and may be used for the assay of D-3-hydroxybutyrate in a variety of physiological and experimental samples.

3-Hydroxybutyric Acid↗
PubMed1984

Determination of ketone body turnover in vivo with stable isotopes, utilizing gas chromatography/mass spectrometry.

JH imple and reliable method for the determination of ketone body turnover in vivo using a primed, continuous infusion of [3,4-13C2]acetoacetate is described. Mole percent enrichment of beta-[13C2]hydroxybutyrate and [13C2]acetoacetate is determined by gas chromatography/mass spectrometry using electron-impact ionization and selected ion monitoring. Ketone body flux data are provided from preliminary dog experiments. The method is readily applicable to the study of ketone body metabolism in both laboratory animals and humans.

3-Hydroxybutyric Acid↗
PubMed1985

A radiochemical assay for acetoacetyl-CoA synthetase.

A sensitive radiochemical assay is described for the assay of acetoacetyl-CoA synthetase activity in cytosolic extracts. Enzyme activity is measured by the incorporation of 14C from acetoacetate into acetyl carnitine as mediated by acetoacetyl-CoA synthetase, endogenous acetoacetyl-CoA thiolase, and exogenous carnitine acetyl transferase. Separation of 14C-labeled reactants from 14C-labeled acetyl carnitine is achieved by cation-exchange chromatography. The assay is sensitive with less than 10 pmol of product readily detected. Acetoacetyl-CoA synthetase activity was measured in human fibroblasts, 0.12 nmol min-1 mg cytosolic protein-1, and was found to be more than two orders of magnitude below the activity level of acetoacetyl-CoA synthetase in rat liver cytosol, 18.4 nmol min-1 mg cytosolic protein-1. An HPLC method is also described for the purification of [3-14C]acetoacetate.

Acetoacetates↗
PubMed1988

Interference of 3-hydroxyisobutyrate with measurements of ketone body concentration and isotopic enrichment by gas chromatography-mass spectrometry.

Concentrations and 13C2 molar percentage enrichments of blood R-3-hydroxybutyrate and acetoacetate are measured by selected ion monitoring gas chromatography-mass spectrometry. Samples are treated with NaB2H4 to reduce unlabeled and labeled acetoacetate to corresponding deuterium-labeled RS-3-hydroxybutyrate species. Only the gas chromatographic peak for the tert-butyldimethylsilyl derivative of 3-hydroxybutyrate needs to be monitored. The various compounds are quantitated using an internal standard of RS-3-hydroxy-[2,2,3,4,4,4-2H6]-butyrate. Concentrations of ketone bodies are obtained by monitoring the m/z 159 to 163 fragments of tert-butyldimethylsilyl derivatives of labeled and unlabeled 3-hydroxybutyrate species. High correlations were obtained between ketone body concentrations assayed (i) enzymatically with R-3-hydroxybutyrate dehydrogenase and (ii) by gas chromatography-mass spectrometry. The limit of detection is about 10 nmol of substrate in blood samples. The current practice of monitoring the m/z 275 to 281 fragments overestimates the concentration of endogenous R-3-hydroxybutyrate, due to co-elution of 3-hydroxyisobutyrate, a valine metabolite. The method presented is used to measure ketone body turnover in vivo in 24-h-fasted dogs.

3-Hydroxybutyric Acid↗
PubMed1985

Mechanisms of uptake of ketone bodies by luminal-membrane vesicles.

The energetics and location of renal transport of acetoacetate, beta-hydroxybutyrate, alpha-hydroxybutyrate and gamma-hydroxybutyrate by luminal-membrane vesicles from either whole cortex or pars convoluta or pars recta of rabbit proximal tubule were studied. Addition of either acetoacetate or beta-hydroxybutyrate or its analogues to dye-membrane-vesicle suspensions in the presence of Na+ gradient (extravesicular greater than intravesicular) resulted in absorbance changes indicative of depolarizing event(s). Valinomycin enhanced the Na+-dependent uptake of monocarboxylic acids, provided a K+ gradient (intravesicular greater than extravesicular) was present. By contrast, Na+-dependent uptake of these compounds was nearly abolished by ionophores that permit Na+ to pass through the luminal-membrane via another channel, either electrogenically (e.g. gramicidin D) or electroneutrally (e.g. nigericin). These results established that the Na+-dependent transport of ketone bodies and analogues by luminal-membrane vesicles is an electrogenic process. Eadie-Hofstee analysis of saturation kinetic data suggested the presence of multiple transport systems in vesicles from whole cortex for these compounds. Tubular localization of the transport systems was studied by the use of vesicles derived from pars convoluta and pars recta. In pars recta uptake of all these compounds was mediated by means of a single high affinity common transport system. Uptake of these compounds by vesicles from pars convoluta was carried out via a relatively low affinity but common transport system. The physiological importance of the transport systems is discussed.

Acetoacetates↗
PubMed1987

Ketone body utilization for energy production and lipid synthesis in isolated rat brain capillaries.

Isolated brain capillaries from 2-month-old rats were incubated for 2 h in the presence of [3-14C]acetoacetate, D-3-hydroxy[3-14C]butyrate, [U-14C]glucose, [1-14C]acetate or [1-14C]butyrate. Labelled CO2 was collected as an index of oxidative metabolism and incorporation of label precursors into lipids was determined. The rate of CO2 production from glucose was slightly higher than from the other substrates. Interestingly, acetoacetate was oxidized at nearly the same rate as glucose. This shows that ketone bodies could be used as a source of energy by brain capillaries. Radiolabelled substrates were also used for the synthesis of lipids, which was suppressed by the addition of albumin. The incorporation of [U-14C]glucose in total lipids was 10-times higher than that from other precursors. However, glucose labelled almost exclusively the glycerol backbone of phospholipids, especially of phosphatidylcholine. Ketone bodies as well as glucose were incorporated mainly into phospholipids, whereas acetate and butyrate were mainly incorporated into neutral lipids. The contribution to fatty acid synthesis of various substrates was in the following order: butyrate greater than or equal to acetate greater than ketone bodies greater than or equal to glucose. All precursors except glucose were used for sterol synthesis. Glucose produced almost exclusively the glycerol backbone of phospholipids.

3-Hydroxybutyric Acid↗
PubMed1975

Alterations in the metabolism of fats and phosphatides in rat liver induced by halide ions.

The effects of halide ions on several pathways of lipid metabolism have been investigated in rat liver slices. Through the use of carboxyl-14-C-labeled acetate and palmitate and U-14-C-labeled glycine, striking differences were found when the effects of the four halide ions on the labeling of the lipids were compared. Both fluoride and iodide dpressed [14-C]acetate incorporation into phosphatide and triglyceride fractions. The effects of the halide ions on the labeling from the effects observed when [14-C]acetate was the precursor of the lipid molecule. In contrast with the phospholipid fractions, the level of radioactivity from [14-C]palmitate incorporated into the triglycerides was lower with fluoride than with chloride. The incorporation of [14-C]glycine into the phospholipids was also greatly depressed by fluoride. The effects of halide ions on acetoacetate formation, on 14-CO2 production and on the acetylcoenzyme A synthetase of rat liver were also investigated. Decreasing [I-14-C]-acetate conversion to acetoacetate iodide had an opposite effect on 14-CO2 production from the same labeled substrate. The effects of the four halide ions and the differences observed with the three labeled substrates on several pathways related to lipid metabolism are discussed.

Acetates↗
PubMed1985

Reference values of blood components related to fuel metabolism in children after an overnight fast.

The interrelation between blood components, involved in fuel metabolism, and age, sex and glucose was studied in 72 control children (26 girls and 46 boys, aged between 3 and 15 yr) after an overnight fast (14 h). Glucose, lactate, pyruvate, triglycerides and cholesterol are age-independent. Alanine is positively correlated, whereas beta-hydroxybutyrate, acetoacetate and NEFA's are negatively correlated with age. With respect to blood sugar, acetoacetate, NEFA's and cholesterol are glucose-independent. Lactate, pyruvate, alanine and triglycerides are positively correlated with glucose, and beta-hydroxybutyrate--and total ketone bodies--are negatively correlated with glucose. Except for triglycerides, no differences in the concentrations of the above mentioned blood substrates are seen between boys and girls. These data demonstrate that after an overnight fast lipolysis and ketogenesis already are active in young children, probably related to inadequate gluconeogenesis and improvement of carbohydrate regulation with age.

3-Hydroxybutyric Acid↗
PubMed1987

CSF concentration and CSF/blood ratio of fuel related components in children after prolonged fasting.

In order to obtain information about blood and cerebrospinal fluid (CSF) concentrations, and CSF/blood ratio data of fuel related substrates at the end of a prolonged fast in children, we have selected biochemical data from fasting test procedures in 11 control children aged 3-5 yr, fasted 24 h, and 58 control children aged 6-15 yr, fasted 40 h. There was a good correlation between blood and CSF concentrations for glucose, acetoacetate and beta-hydroxybutyrate. The relation with age and sex has been analyzed only in the older children. CSF and blood values for glucose are positively related with age, and both ketones are negatively related with age. Lactate, pyruvate and alanine concentrations in blood and CSF are not related with age, except for CSF pyruvate. With respect to the CSF/blood ratio for the above mentioned components, only the value for acetoacetate is sex and age related. The calculated median caloric values for the sum of glucose, lactate, pyruvate and ketones in CSF are independent of age at the end of a 40-h fast. The diminished glucose contribution on the CSF caloric homeostasis in younger children is fully compensated by the ketone bodies.

Acetoacetates↗
PubMed1987

Ketone bodies inhibit leucine degradation in chick skeletal muscle.

1. DL-beta-hydroxybutyrate (4 mM) increased the net rate of leucine transamination and the net rate of 2-oxoisocaproate (KIC) production in extensor digitorum communis muscles from fed chicks. 2. DL-beta-hydroxybutyrate at 1 and 4 mM inhibited leucine oxidative decarboxylation in muscles from fed chicks. 3. Acetoacetate at 1 and 4 mM inhibited leucine oxidative decarboxylation and total leucine oxidation, but increased net KIC production in muscles from fed chicks. 4. Both DL-beta-hydroxybutyrate and acetoacetate at 1 and 4 mM inhibited the net rate of leucine transamination and the rates of leucine oxidative decarboxylation and total leucine oxidation in muscles from 24-hr fasted chicks.

Acetoacetates↗