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PubMed1984

A double-isotope method for the measurement of ketone-body turnover in the rat. Effect of L-alanine.

The synthesis of 4-3H-labelled ketone bodies, and their use along with 14C-labelled ketone-body precursors, is employed using an 'in vivo' rat infusion model to measure ketone-body turnover. The use of two isotopes is necessary to measure ketone-body turnover when ketogenesis may occur from more than one precursor such as glucose and fatty or amino acids. Requirements of isotopic equivalence in terms of metabolic similarity, valid stoichiometry and the lack of differences in the kinetics of relevant enzymes is demonstrated for the 4-3H- and 14C-labelled ketone bodies. The hypoketonaemic effect of L-alanine is shown by two distinct phases after the administration of L-alanine. During the first 12 min after alanine administration ther was a 50% decrease in acetoacetate and a 30% decrease in 3-hydroxybutyrate production, with no significant change in the utilization of either compound. The hypoketonaemic action of alanine during the following 16 min was primarily associated with an uptake of 3-hydroxybutyrate that was somewhat greater than the increase in its production. There were essentially equivalent decreases in production and utilization of acetoacetate, resulting in no significant net change in the level of this ketone body in the blood.

3-Hydroxybutyric Acid↗
PubMed1984

Competition among oxidizable substrates in brains of young and adult rats. Whole homogenates.

The rates of conversion into 14CO2 of D-(-)-3-hydroxy[3-14C]butyrate, [3-14C]acetoacetate, [6-14C]glucose and [U-14C]glutamine were measured in the presence and absence of unlabelled alternative oxidizable substrates in whole homogenates from the brains of young and adult rats. The addition of unlabelled glutamine resulted in decreased 14CO2 production from [6-14C]glucose in brain homogenates from both young and adult rats. In contrast, glucose had no effect on [U-14C]glutamine oxidation. In suckling animals, both 3-hydroxybutyrate and acetoacetate decreased the rate of oxidation of [6-14C]glucose, but in adults only 3-hydroxybutyrate had an effect, and to a lesser degree. The addition of unlabelled glucose markedly enhanced the rates of oxidation of both ketone bodies in adult brain tissue and had little or no effect in the young. The rate of production of 14CO2 from [U-14C]glutamine was increased by the addition of unlabelled ketone bodies in brain homogenates from young, but not from adult rats. In the converse situation, unlabelled glutamine added to 14C-labelled ketone bodies diminished 14CO2 production in young rats, but had no effect in adult animals. These results revealed a complex age-dependent pattern of interaction in which certain substrates apparently competed with each other, whereas an enhanced rate of 14CO2 production was found with others.

3-Hydroxybutyric Acid↗
PubMed1984

The effects of insulin and glucagon on ketone-body turnover.

A double-isotope procedure was used to measure the effects of insulin and glucagon on ketone-body production and utilization (i.e. turnover) in the starved rat. Somatostatin was infused during the experiment to suppress the pancreatic release of either hormone. The immediate action of insulin in terms of ketone-body turnover that was most evident was a decreased production of 3-hydroxybutyrate, with no significant change in the turnover of acetoacetate. Similarly, the significant effect of glucagon infusion was to increase the production of 3-hydroxybutyrate, with minimum increase in acetoacetate turnover. The data support a direct effect of both hormones on the distribution of acetyl units derived from fatty acid beta-oxidation.

3-Hydroxybutyric Acid↗
PubMed1989

Human forearm arteriovenous differences of carnitine, short-chain acylcarnitine and long-chain acylcarnitine.

1. Forearm arterial and venous concentrations of free carnitine, short-chain acylcarnitine, long-chain acylcarnitine, glucose, lactate, pyruvate, alanine, non-esterified fatty acids, glycerol, 3-hydroxybutyrate and acetoacetate were measured in fasted adult subjects. 2. In all subjects there was net uptake of short-chain acylcarnitine, 3-hydroxybutyrate and acetoacetate and net release of free carnitine and non-esterified fatty acids. The arteriovenous differences of the other metabolites were not consistent. 3. These observations support the concept that short-chain acylcarnitine (largely acetylcarnitine) contributes to the flux of metabolic fuels from the liver to muscle in the fasted state, although to a limited extent in comparison with 3-hydroxybutyrate (less than 5% on a molar basis).

3-Hydroxybutyric Acid↗
PubMed1990

Ketone body metabolism in lean male adults during short-term starvation, with particular reference to forearm muscle metabolism.

1. Thirty-three arteriovenous forearm catheterization studies were carried out in 19 lean subjects starving for 12-14 h (n = 13), 30-36 h (n = 7) and 60-66 h (n = 13). Forearm blood flow was measured in order to calculate the flux of various substrates. At the same time, whole-body oxidation of fat, carbohydrate and protein was calculated using indirect calorimetry and urinary nitrogen excretion. 2. After an overnight fast (12-14 h), whole-body resting energy expenditure was accounted for by the oxidation of protein (15%), carbohydrate (17%) and fat (68%). At 30-36 h and 60-66 h of starvation, essentially all the non-protein energy was derived from the oxidation of fat (directly plus indirectly via ketone bodies). 3. After an overnight fast, acetoacetate and 3-hydroxybutyrate were taken up by forearm muscle at a rate which could account for 5% of the resting O2 consumption of this tissue. As starvation progressed, forearm muscle took up more acetoacetate and released 3-hydroxybutyrate so that the net uptake of ketone bodies was sufficient to account for about 10% of the resting O2 consumption at 30-36 h of starvation and about 20% at 60-66 h of starvation.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗
PubMed2003

Time empty and ketone body status in the early postpartum period of dairy cows.

This study aimed to assess the effect of ketone body status early postpartum on time empty in 74 multiparous dairy cows under field conditions. Animals were equally distributed across eight farms and were controlled by the same herd-fertility-monitoring programme. Cows were visited twice antepartum and six times postpartum at weekly intervals between 0530 and 0830 a.m. On these occasions, body condition scores and milk yields were measured, blood and milk samples were taken, cows were gynaecologically examined, and parameters of reproduction were recorded. Cows with a time empty of less or more than 80 days were classified as early and late conceiving cows (EC and LC, respectively). A time empty of 80 days results in calving-to-calving intervals of 1 year and classification based on this threshold value resulted in groups of equal size and equal distribution of EC and LC within farms. Ketone bodies measured were beta-hydroxybutyrate in blood and acetoacetate and acetone in blood and milk. Blood and milk ketone body concentrations, as well as the ratios of acetoacetate and acetone to beta-hydroxybutyrate, over the first 6 weeks postpartum were higher in LC than in EC, whereas plasma glucose and non-esterified fatty acids and milk fat, protein and urea concentrations did not exhibit clear differences between groups. Ketone body concentrations were as good predictors of time empty as ketone body ratios and might have practical impact in herd-fertility-monitoring programmes.

Acetoacetates↗
PubMedDate not supplied

Use of some novel alternative electron sinks to inhibit ruminal methanogenesis.

Several compounds were evaluated in vitro as alternative electron sinks to ruminal methanogenesis. They were incubated with ruminal fluid, buffer mixture, and finely ground alfalfa hay for 24 h, at 0, 6, 12, and 18 mM initial concentrations. The propionate enhancer oxaloacetic acid, the butyrate enhancer beta-hydroxybutyrate, and the butyrate unsaturated analog 3-butenoic acid were ineffective in decreasing methanogenesis. Nevertheless, beta-hydroxybutyrate increased apparent fermentation of the alfalfa hay substrate from 58.0 to 63.4%, and 3-butenoic acid seemed to increase it from 62.0 to 73.7%. Almost all of added oxaloacetic acid disappeared during the incubation, while only between 30.3 and 53.4% of beta-hydroxybutyrate disappeared. The butyrate enhancers acetoacetate and crotonic acid, and the butyrate unsaturated analog 2-butynoic acid, decreased methanogenesis by a maximum of 18,9 and 9%, respectively. Crotonic acid at 18 mM initial concentration seemed to increase the substrate apparent fermentation from 57.0 to 68.2%. Between 78.6 and 100% of acetoacetate disappeared during the incubation. The propionate unsaturated analog propynoic acid, and the unsaturated ester ethyl 2-butynoate, decreased methanogenesis by a maximum of 76 and 79%, respectively. Less than 5% of propynoic acid disappeared. The substrate apparent fermentation was decreased by propynoic acid from 62.0 to 57.4%, and seemed to have been decreased by ethyl 2-butynoate from 62.0 to 29.3%. More accurate measurements of the disappearance of some of the compounds studied are needed to better understand how they are metabolized and how they affect fermentation.

3-Hydroxybutyric Acid↗
PubMed2004

Hydrolytic polyketide shortening by ayg1p, a novel enzyme involved in fungal melanin biosynthesis.

The pentaketide 1,3,6,8-tetrahydroxynaphthalene (T4HN) is a key precursor of 1,8-dihydroxynaphthalene-melanin, an important virulence factor in pathogenic fungi, where T4HN is believed to be the direct product of pentaketide synthases. We showed recently the involvement of a novel protein, Ayg1p, in the formation of T4HN from the heptaketide precursor YWA1 in Aspergillus fumigatus. To investigate the mechanism of its enzymatic function, Ayg1p was purified from an Aspergillus oryzae strain that overexpressed the ayg1 gene. The Ayg1p converted the naphthopyrone YWA1 to T4HN with a release of the acetoacetic acid. Although Ayg1p does not show significant homology with known enzymes, a serine protease-type hydrolytic motif is present in its sequence, and serine-specific inhibitors strongly inhibited the activity. To identify its catalytic residues, site-directed Ayg1p mutants were expressed in Escherichia coli, and their enzyme activities were examined. The single substitution mutations S257A, D352A, and H380A resulted in a complete loss of enzyme activity in Ayg1p. These results indicated that the catalytic triad Asp352-His380-Ser257 constituted the active-site of Ayg1p. From a Dixon plot analysis, 2-acetyl-1,3,6,8-tetrahydroxynaphthalene was found to be a strong mixed-type inhibitor, suggesting the involvement of an acyl-enzyme intermediate. These studies support the mechanism in which the Ser257 at the active site functions as a nucleophile to attack the YWA1 side-chain 1'-carbonyl and cleave the carbon-carbon bond between the naphthalene ring and the side chain. Acetoacetic acid is subsequently released from the Ser257-O-acetoacetylated Ayg1p by hydrolysis. An enzyme with activity similar to Ayg1p in melanin biosynthesis has not been reported in any other organism.

Acetoacetates↗
PubMed1997

Effect of ketone bodies on crop emptying in the chicken.

1. The effect of ketone bodies on crop emptying was studied in chickens in 2 experiments. In the first, the effect of beta-hydroxybutyrate, acetoacetate or acetone on relative crop content was measured. The effects of dietary medium and long chain triacylglycerols upon serum beta-hydroxybutyrate were investigated in the second. 2. beta-Hydroxybutyrate, but not acetoacetate and acetone, delayed crop emptying in a dose dependent fashion. Serum beta-hydroxybutyrate concentration was high in chicks given medium chain triacylglycerol, when compared with long chain triacylglycerol. 3. The results suggest that delayed crop emptying induced by medium chain triacylglycerol could partly be explained by an enhanced concentration of serum beta-hydroxybutyrate, which is the result of the rapid oxidation of medium chain fatty acids.

3-Hydroxybutyric Acid↗
PubMed1978

The role of the kidney in the removal of ketone bodies under different acid-base status of the rat.

Arterial blood concentrations of ketone bodies, pyruvate, lactate, citrate, and oxoglutarate were measured in normal and in nephrectomized rats. The rate of removal from the circulation of an infused acetoacetate load has been studied in both groups of animals. Blood oxoglutarate and ketone bodies remained unchanged in nephrectomized rats. Blood citrate level rose rapidly. In rats with normal blood pH the contribution of the kidneys to the removal of ketone bodies is 28%, whereas in metabolic alkalosis, it is less than 2%. In nephrectomized rats with normal blood pH and in rats with metabolic alkalosis the ratio between beta-hydroxybutyrate and acetoacetate is very high in comparison with rats having metabolic acidosis. These data suggest that in metabolic alkalosis the kidneys are not able to utilize ketone bodies.

Acetoacetates↗
PubMed1997

Megaplasmid and chromosomal loci for the PHB degradation pathway in Rhizobium (Sinorhizobium) meliloti.

Chromosomal and megaplasmid loci that affect the poly-3-hydroxybutyrate (PHB) degradation pathway in Rhizobium meliloti were identified. A clone that restores the ability of certain R. meliloti mutants with defined deletions in megaplasmid pRmeSU47b to use 3-hydroxybutyrate or acetoacetate as the sole carbon source was isolated from a cosmid library of R. meliloti genomic DNA. Tn5 insertion mutagenesis, followed by merodiploid complementation analysis, demonstrated that the locus consists of at least four transcriptional units, bhbA-D. We also identified loci involved in 3-hydroxybutyrate and/or acetoacetate utilization by screening for mutants that had lost the ability to use 3-hydroxybutyrate as the sole carbon source while retaining the ability to use acetate (thus ensuring an intact glyoxylate cycle and gluconeogenic pathway). These mutants fell into four classes, as determined by replicon mobilization experiments and genetic linkage in phage transduction; one class corresponded to the bhb locus on pRmeSU47b, two classes mapped to different regions on the chromosome and the fourth, bdhA, represented by a single mutant, mapped to another pRmeSU47b locus, near bacA. The bdhA mutant is deficient in 3-hydroxybutrate dehydrogenase activity.

Acetoacetates↗
PubMed1994

Carbon sources for D-lactate formation in rat liver.

Carbon sources for D-lactate formation were investigated in vitro using 6,000 x g supernatant of rat liver homogenate and by rat liver perfusion in situ. As carbon sources, L-threonine, glucose, glycerol, acetone, and acetoacetate were tested. Glycerol was the best substrate for D-lactate formation via methylglyoxal in rat liver. Glucose was the second most preferred substrate, while L-threonine, acetone, and acetoacetate were poor substrates for D-lactate formation. Glycerol was several times more effective than normal as a substrate of D-lactate in the supernatants of liver homogenates of diabetic and starved rats, while it was less effective as a substrate of L-lactate. The glycerol kinase [EC 2.7.1.30] activities in livers increased in the diabetic and starved states. These and other results can explain why the plasma concentration of D-lactate increases several-fold after running and why the D-lactate contents in plasma, liver, and skeletal muscle are markedly increases in diabetic and starved rats.

Acetoacetates↗
PubMed1998

Effects of dichloroacetate on mechanical recovery and oxidation of physiologic substrates after ischemia and reperfusion in the isolated heart.

The effects of dichloroacetate (DCA) on fatty acid oxidation and flux through pyruvate dehydrogenase (PDH) were studied in ischemic, reperfused myocardium supplied with glucose, long-chain fatty acids, lactate, pyruvate, and acetoacetate. The oxidation rates of all substrates were determined by combined 13C nuclear magnetic resonance (NMR) spectroscopy and oxygen-consumption measurements, and PDH flux was assessed by lactate plus pyruvate oxidation. In nonischemic control hearts, DCA increased PDH flux more than eightfold (from 0.68 +/- 0.28 to 5.81 +/- 1.16 micromol/min/g dry weight; n = 8 each group; p < 0.05) and significantly inhibited the oxidation of acetoacetate and fatty acids. DCA also improved mechanical recovery after 30 min of ischemia plus 30 min of reperfusion but did not significantly increase PDH flux measured at the end of the reperfusion period (1.35 +/- 0.42 micromol/min/g dry weight) compared with untreated ischemic hearts (0.87 +/- 0.28 micromol/min/g dry weight; n = 8 each group; p = NS). Although DCA had a modest effect on functional recovery in the reperfused myocardium, this beneficial effect was not associated with either marked stimulation of PDH flux or inhibition of fatty acid oxidation.

Acetoacetates↗
PubMed2004

Ketone bodies could support the motility but not the acrosome reaction of mouse sperm.

Ketone bodies, D-beta-hydroxybutyrate and acetoacetate, produced by the metabolism of fatty acids, are an important energy source for many organs, especially the heart, kidney and brain. They are utilized by the body with the help of succinyl CoA transferase (SCOT), which is ubiquitously expressed in various organs. Previously, we identified a novel SCOT-t specifically expressed in testicular germ cells and sperm, substituting somatic cell-type SCOT, however the physiological role of SCOT-t had not then been clarified. In the present study, we investigated the effects of ketone bodies, the substrate of SCOT-t, on the motility and acrosome reaction of mouse sperm. D-beta-hydroxybutyrate and acetoacetate both stimulated the motility of sperm as glucose or pyruvate. The glycolysis inhibitor stopped the motility of sperm mediated by glucose but not by D-beta-hydroxybutyrate. In contrast, ketone bodies did not stimulate the activation of the acrosome reaction of sperm, different from the effect of glucose. These results indicate that ketone bodies could be involved in sperm movement but not the acrosome reaction and the SCOT-t enzyme we have identified in sperm mitochondria may have important roles in the activity of sperm, resulting in male infertility when its function is disabled.

3-Hydroxybutyric Acid↗
PubMed1995

Indicators of histohypoxia.

Cellular tissue damage due to inadequate oxygen supply is frequently encountered in the critically ill patient and can be the end result of a number of conditions. The eventual disruption to the normal processes required for the cell to survive can be due either to the hypoxic state per se or by damage caused during reperfusion of the tissue. Blood gas analysis is commonly used as a macro indicator of oxygen supply, state of art blood gas analysers provide information for oxygen tension (pO2), haemoglobin oxygen saturation (SO2) and concentration (THb), ideally, in arterial and mixed venous blood. The concurrent measurement of carbon dioxide tension (pCO2) and pH will allow the calculation of variables which assist in differentiating between respiratory and non-respiratory conditions. Measurement of cardiac output and clinical assessment of the patients' oxygen requirements will complete the macro picture of supply and demand and although computed indicators of hypoxia have been improved in recent years (1, 2) the definitive diagnosis of histohypoxia requires the measurement of the cellular and subcellular products of metabolic processes that are present when an inappropriate concentration of oxygen has been experienced. However, increases, for example, in blood lactate concentration can occur when an ischaemic area is reperfused and it is argued conversely, that the absence of hyperlactataemia in conditions such as acute respiratory distress syndrome does not necessarily preclude delivery dependence of oxygen consumption with the attendant potential for tissue hypoxia (3). Nevertheless there is general agreement that blood lactate levels can serve as a reliable clinical guide to therapy (4). The laboratory measurement of the metabolic products that accumulate when cellular oxygen supply is limited has become far less labour intensive and with the development of increasingly sophisticated instrumentation, these analytes can be available in small to medium hospital laboratories as well as the larger units. The relatively rapid and accurate analysis of metabolites that accumulate in hypoxic states has allowed us to measure concentrations of blood lactate, pyruvate, beta-hydroxybutyrate and acetoacetate and calculate the lactate/pyruvate ratio and beta-hydroxybutyrate/acetoacetate ratio. These measurements and ratios can then be compared with the non invasive macro blood gas indicators in order to determine their effectiveness as additional "routine" investigations and to indicate how each of the variables contributes to the eventual diagnosis. The parameters used in this study are as follows: Oxygen tension-pO2, Haemoglobin oxygen saturation-SaO2, Haemoglobin concentration-THb, Hydrogen ion concentration as-pH, Concentration of extractable oxygen-Cx, Oxygen extraction tension-px, Conditional extraction at an assumed pvO2 = 30 mmHg-C(a-30)O2, Lactate and pyruvate, beta-hydroxybutyrate and acetoacetate.

3-Hydroxybutyric Acid↗
PubMedDate not supplied

Plasma immunoreactive somatostatin is elevated in diabetic ketoacidosis and correlates with plasma non-esterified fatty acid concentration.

In experimental diabetes and after the administration of beta-hydroxybutyrate and non-esterified fatty acids (NEFA), an increase in circulating immunoreactive somatostatin (IRS) has been described. Both ketones and NEFA are raised in diabetic ketoacidosis. Therefore, we decided to investigate 10 patients in diabetic ketoacidosis by measuring, on admission and throughout the initial 24 hours of therapy, circulating levels of IRS, beta-hydroxybutyrate, acetoacetate, triglycerides, blood glucose, pH and NEFA. Fluids and insulin were administered IV following a previously established protocol. Nine patients showed abnormally high levels of circulating IRS. When compared with a group of controlled insulin-dependent diabetic patients, basal IRS was high (111 +/- 15 vs 28 +/- 3 pmol/l), and remained elevated for at least 24 h despite clear improvement of metabolic status. On admission we also found elevated levels of NEFA (1.04 +/- 0.2 mmol/l), triglycerides (4.7 +/- 1.1 mmol/l), beta-hydroxybutyrate (22.1 +/- 4mmol/l), and acetoacetate (4.8 +/- 1.1 mmol/l). A significant correlation was found initially between IRS and NEFA (p less than 0.01). We conclude that circulating IRS is high in most cases of diabetic ketoacidosis. The mechanism behind this hypersomatostatinaemia could be related to the abnormalities of lipid metabolism which occur in diabetic ketoacidosis.

3-Hydroxybutyric Acid↗
PubMedDate not supplied

Effect of ketones and glucose on the estimation of urinary creatinine: implications for microalbuminuria screening.

The influence of acetoacetate, 3-hydroxybutyrate, and glucose on the assay of urinary creatinine by Jaffé-type and enzymatic methods was studied in vitro. Acetoacetate (greater than or equal to 5 mmol l-1) led to significant overestimation of low concentration urinary creatinine measured by an end-point and a kinetic Jaffé reaction, but neither 3-hydroxybutyrate nor glucose influenced these reactions. None of the metabolites interfered with an enzymatic creatininase assay. It is recommended that, when employing the urinary albumin/creatinine ratio to screen for microalbuminuria in diabetes mellitus, an enzymatic method be used to measure creatinine in Ketostix positive samples, particularly those that are dilute or obtained from patients with a low lean body mass.

3-Hydroxybutyric Acid↗
PubMed1988

Ketone body utilization for lipid synthesis in the murine sciatic nerve: alterations in the dysmyelinating trembler mutant.

This work demonstrates that in vitro sciatic nerves of normal and trembler adult mice can use ketone bodies (beta-hydroxybutyrate and acetoacetate) and butyrate for lipid synthesis. In normal sciatic nerves, beta-hydroxybutyrate is incorporated in total lipids to a larger extent than acetoacetate (141% and 33%, respectively, of acetate incorporation), whereas for trembler sciatic nerves, these percentages are only 69% and 27%. Incorporation of ketone bodies is greater into sterols than into other lipids. Lipid metabolism of ketone bodies in trembler nerves is altered and could reflect a process similar to Wallerian degeneration: a dramatic decrease of sterol and free fatty acid synthesis and an increased synthesis of triglycerides. Moreover, differences seen in precursor incorporation into lipids between normal and trembler sciatic nerves suggest that their lipid metabolism is not the same.

3-Hydroxybutyric Acid↗