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PubMed1989

Kidney hemodynamics after ketone body and amino acid infusion in normal and IDDM subjects.

Little information is available on the hemodynamic response (renal reserve) of the diabetic kidney during an acute amino acid infusion, which has been shown to increase glomerular filtration rate (GFR) in normal humans. We recently found that the infusion of ketone bodies is able to raise GFR in both normal subjects and insulin-dependent diabetes mellitus (IDDM) patients. The aim of this study was to evaluate the renal reserve in 15 IDDM patients with a duration of diabetes of greater than 9 yr [8 with albumin excretion rate less than 15 micrograms/min (group 1) and 7 with albumin excretion rate greater than 100 micrograms/min (group 2)] and in 8 normal subjects during amino acid infusion (33 mumol.kg-1.min-1, Travasol 10% wt/vol solution containing 0.154 mM sodium chloride concentration; Travenol, Savage, MD) and during acetoacetic sodium salt (25 mumol.kg-1.min-1) infusion. Blood glucose was clamped at euglycemic levels. The infusion of sodium acetoacetate resulted in a 10- to 15-fold increase in circulating concentrations of ketone bodies, which were similar in magnitude in normal subjects and diabetic patients. The GFR peak increase above baseline after sodium acetoacetate infusion was 28% in normal subjects and 27% in group 1 and 19% in group 2 diabetic patients. The infusion of amino acid solution produced a three- to fivefold increase in plasma concentrations of amino acids in both normal subjects and diabetic patients. The GFR peak increase above baseline after amino acid infusion was significantly lower in diabetic patients (IDDM group 1: 5%, P less than .01; IDDM group 2: 6%, P less than .01) than in normal subjects (38%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Effect of increasing ruminal butyrate on portal and hepatic nutrient flux in steers.

Six Holstein steers (mean +/- SE BW = 344 +/- 10 kg) fitted with hepatic, portal, and mesenteric vein and mesenteric artery catheters and a ruminal cannula were used in a 6 x 6 Latin square design to evaluate the effects of increasing ruminal butyrate on net portal-drained visceral and hepatic nutrient flux. Steers were fed a 40% brome hay, 60% concentrate diet in 12 portions daily at 1.25 x NEm. Water (control) or butyrate at 50, 100, 150, 200, or 250 mmol/h was supplied continuously via the ruminal cannula. Simultaneous arterial, portal, and hepatic blood samples were taken at hourly intervals from 15 to 20 h of ruminal infusion. Portal and hepatic blood flow was determined by continuous infusion of P-aminohippurate, and net nutrient flux was calculated as the difference between venous and arterial concentrations times blood flow. Ruminal and arterial concentrations and total splanchnic flux of butyrate increased (P less than .01) with increased butyrate infusion. Arterial concentrations of acetate (P less than .10), alpha-amino-N (P less than .05), and glucose (P less than .01) decreased with increased butyrate, whereas arterial beta-hydroxybutyrate (P less than .01) and acetoacetate (P less than .05) increased. Increased butyrate produced an increased portal-drained visceral flux of acetoacetate and an increased net hepatic flux of beta-hydroxybutyrate. Urea N and glucose net portal and hepatic fluxes were not affected by ruminal butyrate. Alpha-amino-N uptake by the liver decreased with increased butyrate (P less than .10). Simple linear regression (r2 = .985) indicated that 25.8% of ruminally infused butyrate appeared in portal blood as butyrate. Only 14% could be accounted for as net portal-drained visceral flux of acetoacetate plus beta-hydroxybutyrate.

Ammonia↗
PubMed2002

Detection of ketosis in vitreous at autopsy after embalming.

Ketosis occurs in ketoacidosis or malnourishment. When either is suspected in relation to a death, it may be important to analyze for ketosis at autopsy. We encountered a case where starvation was suspected in a deceased nursing home resident, where the body had been embalmed prior to autopsy. Gas chromatography (GC) was unable to separate acetone from formaldehyde, a component of embalming fluid. The Acetest is a simple test that can detect acetone and acetoacetate in body fluids. We validated the Acetest with GC on vitreous. The Acetest and GC were consistent except at very low levels of acetone or acetoacetate. The sensitivity of the Acetest for acetoacetate in vitreous was 10 mg/dL, consistent with early starvation. Significant interference from embalming fluid did not occur. The Acetest was negative in the described case. The Acetest is a simple and useful test for the detection of ketosis in embalmed autopsies.

Aged↗
PubMed1977

Purification and properties of 3-keto-5-aminohexanoate cleavage enzyme from a lysine-fermenting Clostridium.

The lysine-fermenting Clostridium SB4 is shown to contain a new type of beta-keto acid-degrading enzyme that converts 3-keto-5-aminohexanoate and acetyl-CoA reversibly to L-3-aminobutyryl-CoA and acetoacetate. Following the development of a sensitive radiochemical assay the enzyme was purified 175-fold to about 90% homogeneity in 44% yield. The specific activity of the purified enzyme is 44 IU/mg of protein at 30 degrees. The equilibrium constant for the forward reaction was found to be 0.68 at 30 degrees and pH 7.0, corresponding to a deltaG0' of 0.23 kcal/mol. The enzyme is highly substrate-specific. Of several substrate analogs tested in the forward and back reactions only beta-alanyl-CoA and D-3-aminobutyryl-CoA are utilized about 130% and 1.7% as fast as L-3-aminobutyryl-CoA, respectively. The product formed from beta-alanyl-CoA and acetoacetate is a neutral beta-keto acid, presumably 3-keto-5-aminopentanoic acid; its borohydride reduction product was partially characterized as a hydroxy-amino acid by various chromatographic and ion exchange methods. The activity of the purified enzyme is increased about 5-fold by addition of 0.1 mM Co2+ and to a lesser extent by Mn2+. Activity is inhibited by orthophosphate, thiol reagents, and EDTA; however, exposure of the enzyme to the latter compound prior to addition of Co2+ increases activity, presumably by removing competing divalent cations. Tracer experiments have shown that carbon atoms 1 and 2 of acetoacetate are derived from carbon atoms 1 and 2 of 3-keto-5-aminohexanoate whereas carbon atoms 3 and 4 are derived from acetyl-CoA. The amino acid moiety of 3-aminobutyryl-CoA is derived from carbon atoms 3 to 6 of 3-keto-5-aminohexanoate. Since no evidence for covalent enzyme-substrate intermediates could be obtained by the study of four possible group exchange reactions, a concerted reaction between 3-keto-5-aminohexanoate and acetyl-CoA is considered. The enzyme has a molecular weight of about 97,000 and probably contains four identical subunits. The relatively high specific activity of the enzyme in extracts of Clostridium SB4 indicates it functions in the main pathway of lysine degradation. This relatively stable enzyme provides a convenient and specific method for the quantitative estimation of nanomolar amounts of L- and D-3-aminobutyryl-CoA and beta-alanyl-CoA.

Aminocaproates↗
PubMed2006

[Experimental study on anti-tumor effect of extractive from Celastrus orbiculatus in vivo].

OBJECTIVE: To study the anti-tumor activity of extractive from Celastrus orbiculatus in vivo. METHOD: Mice bearing transplanted tumor S180 and Heps were used to study the effects of acetoacetate and n-butanol extractive from C. orbiculatus. The changes in serum contents of SOD and malondialdehyde (MDA) content were assayed. RESULT: Acetoacetate and n-butanol extractive from C. orbiculatus significantly inhibited the growth of S180 and Heps tumor in mice. SOD content was obviously increased, MDA content obviously decreased in the serum after extractive treatment. CONCLUSION: Acetoacetate and n-butanol extractive from C. orbiculatus have anti-tumor effects and anti-oxidative capacity.

Animals↗
PubMed1989

Pyruvate metabolism by lymphocytes: evidence for an additional ketogenic tissue.

The rate of utilization of pyruvate (at various concentrations) was measured in lymphocytes prepared from rat mesenteric lymph nodes. The quantitative contribution of pyruvate to CO2, lactate, aspartate, alanine, citrate, acetate, acetyl-CoA and ketone bodies accounted for the pyruvate metabolized. Pyruvate utilization was depressed by increasing concentrations of pyruvate. The maximum catalytic activities and selected intracellular distributions of the following enzymes of pyruvate, citrate and acetyl-CoA metabolism were measured: citrate synthase, ATP-citrate lyase, lactate dehydrogenase, acetyl-CoA hydrolase, acetylcarnitine transferase, NAD+- and NADP+- isocitrate dehydrogenases, HMG-CoA lyase, HMG-CoA synthase, Pyruvate dehydrogenase, acetoacetyl-CoA thiolase, 3-oxoacid-CoA transferase, 3-hydroxybutyrate dehydrogenase and pyruvate carboxylase. Acetyl-CoA formed from pyruvate did not contribute to the respiratory energy metabolism of resting lymphocytes. Instead acetyl-CoA was converted to acetoacetate by reactions which may favour the pathway catalyzed by acetoacetyl-CoA thiolase and 3-oxoacid-CoA transferase. Acetate, acetyl- and palmitoyl-carnitine inhibited the decarboxylation of [1-14C] pyruvate. These observations may be connected with the suppression of pyruvate utilization by increased pyruvate substrate concentration. Only very small amounts of either pyruvate or acetate were incorporated into lipids in resting lymphocytes. The amounts incorporated were partitioned in approximately the same pattern into FFA, T.G., cholesterol and cholesterol esters. Taken together the data show that pyruvate metabolism is directed inter alia at the formation of acetoacetate which may serve as a lipid synthesis precursor. When pyruvate utilization and metabolism was enhanced by concanavalin A, then acetoacetate formation was not favoured and from this it is proposed that the acetyl units may then be directed into lipid synthesis and may also make a contribution to the energy metabolism of the activated lymphocyte.

Animals↗
PubMed1984

Purification and characterization of acetoacetyl-CoA synthetase from rat liver.

Acetoacetyl-CoA synthetase (acetoacetate:CoA ligase) was purified to electrophoretic homogeneity from a rat liver supernatant by ammonium sulfate fractionation and successive chromatographies on DEAE-Sepharose, Blue-Sepharose, Red-Sepharose, CoA-Sepharose, Ultrogel AcA-44, and DEAE-Sepharose once again. The purified enzyme had a specific activity of 2.3 mumol acetoacetyl-CoA formed per min per mg protein, which constituted a 960-fold purification compared to the crude extract, with a 7.4% yield. The enzyme absolutely required ATP, CoA, a monovalent cation (K+, Rb+, Cs+ or NH4+) and a divalent cation (Mg2+, Mn2+ or Ni2+) for its activity, yielding acetoacetyl-CoA, AMP and PPi in equimolar amounts. The molecular weight of the enzyme was approximately 80 000 as determined by Ultrogel AcA-34 gel filtration, and 71 000 by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. The enzyme was active only on acetoacetate and to a lesser extent on L-(+)-3-hydroxybutyrate, and the Km values for acetoacetate, L-(+)-3-hydroxybutyrate, ATP and CoA were 8 microM, 75 microM, 60 microM and 10 microM, respectively.

Acetyl Coenzyme A↗
PubMed1983

Reduction in mitogenic response of bovine lymphocytes by ketone bodies.

The effect of toxic or subtoxic concentrations of ketone bodies (acetone, beta-hydroxybutyrate, acetoacetate) in blood on function of bovine lymphocytes was studied in vitro. Lymphocytes separated from peripheral bovine blood were distributed into the wells of Linbro Microtiter plates containing control medium and test medium with various concentrations of ketones and/or phytohemagglutinin. The mitogenic response of lymphocytes was measured by incorporation of [3H]thymidine into DNA of lymphocytes. Toxic and subtoxic concentrations of beta-hydroxybutyrate or the toxic concentration of acetoacetate significantly affected the mitogenic response of bovine lymphocytes. The reduction in the mitogenic response also occurred when lymphocytes were only preincubated for 2 hours or longer with beta-hydroxybutyrate or acetoacetate. The presence of the toxic concentration of acetone in the medium did not affect the mitogenic stimulation of lymphocytes.

3-Hydroxybutyric Acid↗
PubMed1981

Pathophysiology of hemorrhagic shock. A role of arterial ketone body ratio as an index of anoxic metabolism of the liver in acute blood loss.

The changes in the oxido-reduction state and the adenylate energy charge of the liver were investigated in rats having 16%, 50%, and 84% mortality rates after acute hemorrhage. In the arterial blood, concentrations of ketone bodies, pyruvate, lactate, and the ratios (acetoacetate to beta-hydroxybutyrate and pyruvate to lactate) were measured after hemorrhage and reinfusion of the shed blood. The mitochondrial oxido-reduction state and the blood ketone body ratio decreased 15 minutes after hemorrhage. The values of these parameters of rats having the higher mortality rate were lower than those rats having the lower mortality rate. In addition, the changes in both the adenylate energy charge and the mitochondria oxido-reduction state of the liver were closely correlated with the changes in the ratio of acetoacetate to beta-hydroxybutyrate in the arterial blood (P less than 0.001). Thus, it is suggested that the decreased oxygen supply to the liver mitochondria may play an important role in determining the mortality rate after acute hemorrhage and is reflected in the ratio of acetoacetate to beta-hydroxybutyrate in the arterial blood.

Acute Disease↗
PubMedDate not supplied

The effect of lactobacilli inoculation on organic acid levels in the mucosal film and the small intestine contents in gnotobiotic pigs.

The effect of the inoculation of three Lactobacillus plantarum strains upon lactic, acetic, acetoacetic and propionic acid levels in the mucosal film (F) and the jejunal and ileal contents (O) has been investigated in gnotobiotic pigs. In the jejunum of the inoculated animals, the mucosal film revealed significantly increased levels of lactic, propionic and acetoacetic acids when compared to the contents (25.3 vs. 10.8 mmol.l-1, 18.5 vs. 5 mmol.l-1 and 29.7 vs. 11.2 mmol.l-1, respectively) as well as insignificantly increased acetic acid levels (11.0 vs. 5.8 mmol.l-1). In the ileum of gnotobiotic pigs, propionic acid levels of the mucosal film were significantly higher than those of the contents (21.2 vs. 9.5 mmol.l-1, p < 0.05). In comparison to the contents, the increased lactic, acetic and acetoacetic acid levels in the film proved to be insignificant. The above results suggest that the significantly increased levels of the Lactobacilli-produced organic acids may present an efficient barrier inhibiting the adherence of digestive tract pathogens to the intestinal mucosa.

Animals↗
PubMed1988

Activation of fatty acid oxidation in the Silver-Russell syndrome and the Brachmann-de Lange syndrome.

We describe a similar metabolic pattern of hyperketosis, ketonaciduria, and C6-C12 dicarboxylic aciduria in a patient with the Silver-Russell syndrome and a patient with the Brachmann-de Lange syndrome. Fasting blood levels of beta-hydroxybutyrate and acetoacetate were significantly higher than in age-matched controls, and both patients showed massive urinary excretion of beta-hydroxybutyrate, acetoacetate and C6-C12 dicarboxylic acids.

3-Hydroxybutyric Acid↗
PubMed1989

Morphometric modifications associated with early sensory experience in the rat olfactory bulb: II. Stereological study of the population of olfactory glomeruli.

The present study explores the local variations of size and number of olfactory glomeruli induced by the exposure of young rats to long-term stimulation with a single odor. Three groups of 5 rats were used that were either: (1) stimulated with ethyl acetoacetate from birth to 1 month of age, (2) unilaterally deprived following early occlusion of one nare, or (3) normal animals of the same age. Areas and coordinates of all glomerular profiles were measured in 14 coronal sections uniformly distributed along the rostrocaudal axis of the olfactory bulb. A distribution-free stereological method was applied to compute the size and number of glomeruli either along the bulbar rostrocaudal extent or in the bulbar coronal plane. Following complete sensory deprivation or long-term stimulation with ethyl acetoacetate, the mean diameter of glomeruli was significantly reduced everywhere, except in the ventrolateral and ventromedial regions of the posterior olfactory bulb in rats reared with a single odor. In both of these areas, the number of glomeruli was either significantly increased following long duration exposure or significantly reduced following unilateral deprivation. Thus these results show that selective modifications of the olfactory environment during postnatal maturation induce morphometric variations in specific areas of the glomerular layer. These data are discussed with respect to the concept of the topographical coding of odor quality at the level of the glomeruli and plasticity of the olfactory system during postnatal development.

Acetoacetates↗
PubMed2001

Glucagon effects on brain carbohydrate and ketone body metabolism of rainbow trout.

The levels of glycogen in brain, lactate and acetoacetate in brain and plasma, glucose in plasma and the activities of brain key enzymes of glycogen metabolism (glycogen phosphorylase, GPase, glycogen synthetase, GSase), gluconeogenesis (fructose 1,6-bisphosphatase, FBPase), and glycolysis (6-phosphofructo 1-kinase, PFK) were evaluated in rainbow trout, Oncorhynchus mykiss, from 0.5 to 3 hr after intraperitoneal injection of 1 ml/kg(-1) body weight of saline alone (controls) or containing bovine glucagon at three different doses: 10, 50, and 100 ng/g(-1) body weight. The results obtained demonstrate, for the first time in a teleost fish, the existence of changes in brain carbohydrate and ketone body metabolism following peripheral glucagon treatment. A clear stimulation of brain glycogenolytic potential was observed after glucagon treatment, as judged by the time- and dose-dependent changes observed in brain glycogen levels (up to 88% decrease), and GPase (up to 30% increase) and GSase (up to 42% decrease) activities. In addition, clear time- and dose-dependent increased and decreased levels were observed in brain of glucagon-treated rainbow trout for lactate (up to 60% increase) and acetoacetate (up to 67% decrease), respectively. In contrast, no significant changes were observed after glucagon treatment in those parameters related to glycolytic/gluconeogenic capacity of rainbow trout brain. Altogether, these in vivo results suggest that glucagon may play a role (direct or indirect) in the regulation of carbohydrate and ketone body metabolism in brain of rainbow trout.

Acetoacetates↗
PubMed1993

N-acetyl-L-aspartate and acetate 1H NMR signal overlapping under mild acidic pH conditions.

The pH dependence of methyl proton chemical shifts of acetate, acetoacetate, N-acetyl-L-aspartate (NAA), and N-acetyl-L-aspartyl-L-glutamate (NAAG) were studied from pH 3 to pH 9. Only slight shifts of acetoacetate, NAA, and NAAG methyl signals were observed, whereas the acetate signal was largely shifted as a result of the titration of its acidic function. At pH 4.7, acetate and NAA methyl signals overlapped, whereas at more acidic pH, the acetate signal appeared downfield when compared to that of NAA. Results are discussed in terms of spectra misinterpretation risks linked to uncontrolled sample pH, on the one hand, and in terms of pH control and contamination by exogenous acetate during perchloric acid cell extract preparation, on the other.

Acetates↗
PubMed1987

Effects of metabolic factors in the diabetic state on the in vitro development of preimplantation mouse embryos.

The effects of insulin, glucagon, beta-hydroxybutyrate, and acetoacetate on the in vitro development of preimplantation mouse embryos were studied. In controls, 24% of blastocysts failed to develop successfully when grown for 72 h in Eagle's medium supplemented with 10% fetal calf serum. Insulin at concentrations of 1.0 and 2.0 IU/ml of culture medium interfered with development in 62-63% of the blastocysts. Preimplantation embryos showed a threshold pattern in their reaction to glucagon: its addition in concentrations of 0.0015 mM (5 micrograms/ml) did not significantly inhibit blastocyst development, while concentrations of 0.003 mM (10 micrograms/ml) inhibited 70% of blastocysts. The embryotoxic effects of ketone bodies were manifested only in relatively high doses. beta-hydroxybutyrate was embryotoxic at concentrations greater than 5 mg/ml, and its effects were dose dependent: 48 mM (6 mg/ml) inhibited 45% of blastocysts, while 80 mM (10 mg/ml) arrested 87% of embryos from further development. Acetoacetate at concentrations of 0.1 mM (10 micrograms/ml) inhibited the development of 50% of the blastocysts, and its effects were not dose dependent: concentrations of 1 mM (100 micrograms/ml) inhibited development in 63% of the embryos. The combination of the diabetic metabolic factors in relatively low concentrations was highly embryotoxic, especially when accompanied by hyperglycemia.

3-Hydroxybutyric Acid↗
PubMed1996

Acyl CoA and lipid synthesis from ketone bodies by the extramitochondrial fraction of hepatoma tissue.

The compartmentation of the pathway for the synthesis of lipids from ketone bodies was examined in a cell free, post-mitochondrial supernatant fraction of malignant Morris hepatoma 7777 tissue. A fortified supernatant system effectively incorporated radioactive D(-)-3-hydroxybutyrate and acetoacetate into cholesterol and fatty acids, and both ketone bodies were directly converted to their CoA thioesters. Furthermore, a microsome-free (100,000 x g) cytosolic fraction was also able to acylate 3-hydroxybutyrate to 3-hydroxybutyryl CoA. No previous identification of this enzyme activity has been described. These results which characterize a distinct extramitochondrial pathway for conversion of 3-hydroxybutyrate as well as acetoacetate into lipids also suggest the possibility of a previously undetected enzymatic activity for utilization of this ketone body.

3-Hydroxybutyric Acid↗
PubMed1999

A predominant increase of arterial beta-hydroxybutyrate concentration during partial hepatectomies in patients with impaired indocyanine green clearance test.

BACKGROUND: It has been reported that a concentration ratio of two ketone bodies, [acetoacetate]/[beta-hydroxybutyrate], reflects the redox state in the liver mitochondria, but there are few reports which examined each ketone body concentration during hepatectomy. Materials and Methods. (1) Ketone body levels in the radial artery and the hepatic vein were measured simultaneously during hepatectomies in 12 patients. (2) Arterial ketone body levels were measured during hepatectomies (at three points) in 73 patients. RESULTS: (1) Both ketone body levels in the radial artery well reflected those in the hepatic vein (P < 0.001). (2) There was no change in the arterial acetoacetate level. The level of beta-hydroxybutyrate increased significantly from 30.4 to 76.5 micromol/L (P < 0.005) only in the group of 25 patients with seriously impaired indocyanine green clearance test. CONCLUSIONS: Ketosis during hepatectomy was caused by increased beta-hydroxybutyrate, and this phenomenon was observed only in patients with seriously impaired liver function.

3-Hydroxybutyric Acid↗
PubMed1996

Altered hepatic metabolism of fatty acids in rats fed a hypolipidaemic drug, fenofibrate.

The aim of this study was to examine the effects of dietary fenofibrate (0.05% in the diet) on ketone body production and lipid secretion in isolated perfused rat liver. Feeding with fenofibrate for 7-9 days caused an increased liver weight. Ketone body production was significantly greater in the livers perfused with oleic acid than in those perfused without fatty acid, with the elevation of the ratio of beta-hydroxybutyrate:acetoacetate indicating an increased redox potential in mitochondrial compartments by exogenous fatty acid. On the other hand, fenofibrate feeding caused a further stimulation of ketone body production from both endogenous and exogenous fatty acid substrates, respectively, with a decreased ratio of beta-hydroxybutyrate:acetoacetate as compared to respective control livers, indicating a decreased redox potential. Hepatic secretion of triglyceride, but not of cholesterol, was decreased markedly in the fenofibrate-fed rats, especially when oleate was provided, suggesting an inverse relationship between rates of ketogenesis and triglyceride secretion. These results suggest that the altered hepatic metabolism of long-chain fatty acids between oxidation and esterification caused by fenofibrate may thus be a factor responsible for the decreased secretion of triglyceride, hence leading to hypotriglyceridaemia in vivo.

Acetoacetates↗