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PubMed1998

Neutrophil chemiluminescence during phagocytosis is inhibited by abnormally elevated levels of acetoacetate: implications for diabetic susceptibility to infections.

Human neutrophils by a chemiluminescence assay exhibit diminished phagocytic activity in the presence of abnormally high levels of the serum metabolite acetoacetate. These findings, along with our previous evidence demonstrating myeloperoxidase inhibition by acetoacetate, implicate metabolic ketosis in the inhibition of neutrophil microbicidal activity and thus in increased susceptibility to infections.

Acetoacetates↗
PubMed1978

Transfer of C2-units across the mitochondrial membrane. Direct recording of citrate, acetate and acetoacetate production rates.

Methods are described for the direct optical assay of citrate, acetate, and acetoacetate production by isolated, incubated rat liver mitochondria. Each metabolite is converted into acetyl-CoA, using ATP: citrate lyase or acetyl-CoA synthetase or acetoacetyl-CoA synthetase and acetyl-CoA acetyltransferase, respectively. Arylamine acetyltransferase acts as auxiliary enzyme. It was shown that isolated rat liver mitochondria produce citrate, acetate and acetoacetate, and that production rates are stimulated by pyruvate and hexanoate. It was concluded that these three products might contribute to the transport of acetyl units across the mitochondrial membrane and thus serve as precursors in fatty acid synthesis. The rate of acetyl transfer does not seem to be rate-limiting with regard to the overall-process of fatty acid synthesis from carbohydrates.

Acetates↗
PubMed2003

Elevated blood interleukin-6 levels in hyperketonemic type 1 diabetic patients and secretion by acetoacetate-treated cultured U937 monocytes.

OBJECTIVE: Diabetic patients have elevated blood levels of interleukin-6 (IL-6), which is known to increase inflammation and the development of vascular disease and atherosclerosis. This study examined the hypothesis that ketosis increases the circulating levels of IL-6 in type 1 diabetic patients as well as the secretion of IL-6 in vitro in a cell culture model using U937 monocytes. RESEARCH DESIGN AND METHODS: Fasting blood was obtained from type 1 diabetic patients and healthy siblings. To examine the effect of ketosis, U937 monocytes were cultured with ketone bodies (acetoacetate [AA], beta-hydroxybutyrate [BHB]) in the presence or absence of high glucose levels in the medium at 37 degrees C for 24 h. IL-6 was determined by the sandwich enzyme-linked immunosorbent assay method, and intracellular reactive oxygen species (ROS) generation was detected using dihydroethidium dye. RESULTS: The blood level of IL-6 was higher in hyperketonemic (HK) diabetic patients than in normoketonemic (NK) diabetic patients (P < 0.05) and normal control subjects (P < 0.05). There was a significant correlation between ketosis and IL-6 levels (r = 0.36, P < 0.04, n = 34) in the blood of diabetic patients. Cell culture studies found that exogenous addition of the ketone body AA, but not BHB, increases IL-6 secretion and ROS generation in U937 cells. N-acetylcysteine (NAC) prevented the IL-6 secretion in acetoacetate-treated U937 monocytes. CONCLUSIONS: This study demonstrates that hyperketonemia increases IL-6 levels in the blood of type 1 diabetic patients and that NAC can inhibit IL-6 secretion by U937 monocytic cells cultured in a ketotic medium.

Acetoacetates↗
PubMed2001

The influence of acetoacetate and butyrate on calcium influx and ATP concentrations in HT-29 cells.

The effects of acetoacetate and butyrate on Ca(2+)-influx in HT-29 cells were unknown. Extracellular signals can be transferred to the intracellular environment of the cell via changes in the Ca(2+)-concentration. Extracellular Ca2+ may enter the cell via Ca(2+)-channels in the plasma membrane. Physiological processes occurring within the cell are dependent on Ca(2+)-concentration, including enzyme activity. Intracellular Ca(2+)-concentrations were measured using Fura-2/AM, a fluorescent intracellular Ca(2+)-probe. Ca(2+)-concentrations were measured immediately on application of the inducers to the cells, as well as after a 9 day incubation period. The effect of these inducers on the L-type voltage-operated Ca(2+)-channels were determined using the whole-cell patch-clamp technique. To validate these results for the intestinal epithelial model, membrane current studies were performed on HT-29 cells grown on a polycarbonate membrane. ATP concentrations were measured, and the theoretical effect of the inducers on PDE 4 activity was determined. It was found that both acetoacetate and butyrate blocked Ca(2+)-influx through the L-type voltage-operated Ca(2+)-channels, resulting in the initial low Ca(2+)-concentration (p < 0.05). The blockage effect is short-lived as after a 9 day incubation period in the presence of the inducers, Ca(2+)-concentrations were higher than that of the HT-29 control sample (p < 0.05). ATP concentrations of the cells were decreased in the presence of the inducers (p < 0.05), whilst it was suggested that no interaction between the catalytic site of PDE 4 and the inducers existed.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1989

Thyroxine in blood plasma related to plasma levels of acetoacetate and glucose in ketotic and healthy cows.

Plasma samples were taken before morning feeding twice weekly for the first 3 months post partum from 28 individually fed cows, of which 8 developed clinical ketosis. Feed rations consisted of grass silage ad libitum and concentrates. The high incidence of ketosis may be accounted for mainly by substandard amounts of feed energy, and by variations in the quality of the grass silage. The following sources of post-partum thyroxine variation were found to be statistically significant (p less than 0.001): The individual cow, the individual pre-calving thyroxine level, metabolic status estimated by plasma levels of acetoacetate or glucose, and elapsed time from partus. The post-partum decrease in thyroxine was greater in cows which developed ketosis (55%) than at the corresponding stage of lactation in those which remained moderately ketonaemic (33%). Extensive overlapping of ranges nevertheless indicates that the apparent hypothyroidism of ketosis is of limited importance for the etiology of the disease. Susceptibility to ketosis was not related to the thyroxine levels observed before partus or after recovery from the disease, in the third month of lactation. Evidence was obtained of a common glucose threshold of about 3.6 mmol/l, below which decreasing sugar levels were accompanied by progressive increments in acetoacetate and decreases in thyroxine. Above the threshold level, the average level of the hormone increased from the first to the third month of lactation in spite of a poor correlation to glucose.

Acetoacetates↗
PubMed1985

Oxidation of acetoacetate and palmitylcarnitine by brain and liver mitochondria from suckling and adult rats.

Experiments in which we investigated the possible oxidative utilization of lipoid substrates by brain and liver mitochondria were carried out with rats aged 5 and 90 days, kept under completely standardized conditions. Brain mitochondria were isolated on a Ficoll gradient after Clark and Nicklas (1970). Respiratory activity (or the respiratory control index-R.C.) was determined in the manner described in an earlier paper (Dobesová and Mourek 1980). Na succinate or Na malate was used as the testing substrate; palmityl carnitine, acetyl carnitine and acetoacetate were used as lipoid substrates. Oxygen consumption was measured with a Clark's oxygen electrode and respiration was expressed in nAt oxygen per min per mg protein, which was measured by the method of Lowry et al. (1951). When using succinate or malate, in agreement with our previous results we did not find any development changes in the respiratory activity of the brain mitochondria. The oxidation of acetoacetate by the brain mitochondria of 5-day-old rats was about five times greater, and of acetyl carnitine over two times greater, compared with the CNS mitochondria of adult rats. The oxidative utilization of lipoid substrates by the liver mitochondria of 5-day-old rats was significantly greater than their utilization by CNS mitochondria (in the case of palmityl carnitine three times greater, for example) and was always significantly greater than in the liver mitochondria of adult rats. We demonstrated that mitochondria isolated from the brain of 5-day-old rats are equipped with an enzymatic apparatus which allows them to utilize lipoid substrates on a significantly greater scale than in adulthood.

Acetoacetates↗
PubMed1986

Uptake of beta-hydroxybutyrate, acetoacetate and glucose by the forearm of the newborn infant.

Forearm muscle metabolism was studied in twelve appropriate for gestational age premature infants suffering from respiratory distress. Arterial blood was obtained by puncture of the radial artery as clinically indicated for measuring oxygen tension, and venous blood samples were taken from the same arm's deep brachial vein. This arrangement allowed to study the arterial-deep venous differences of beta-hydroxybutyrate, acetoacetate and glucose in simultaneously taken blood samples. Net muscular uptakes of beta-hydroxybutyrate and glucose were observed, however, in four studies a virtual net production of acetoacetate was found. The arterial-deep venous concentration differences of both ketone bodies correlated positively with their arterial concentration within the 20 to 120 nanomol/ml range. Such a correlation was not observed in glucose utilization. It is concluded that forearm muscles in the neonate take up ketone bodies and this is in part concentration regulated.

3-Hydroxybutyric Acid↗
PubMed1978

Direct assays of lactate, pyruvate, beta-hydroxybutyrate, and acetoacetate with a centrifugal analyzer.

Methods are described for direct assays of lactate, pyruvate, beta-hydroxybutyrate, and acetoacetate in plasma with the GEMSAEC centrifugal analyzer. The methods for lactate, beta-hydroxybutyrate, and acetoacetate are kinetic and ratiometric, eliminating the need for specimen-blank assays. The pyruvate method is an end-point assay, because endogenous lactate dehydrogenase interferes in a kinetic pyruvate assay. The methods are precise and accurate and 1-min of analysis time is adequate for each assay. Rapid assessment and monitoring of metabolic acidosis is possible with these methods, as is illustrated by examples.

Acetoacetates↗
PubMed1984

Novel surface lipids of diapausing Manduca sexta pupae. Long chain oxoalcohol esters of acetoacetic, hydroxybutyric, and acetic acids.

Ester components in the surface wax from diapausing tobacco hornworm pupae, Manduca sexta L., were separated by thin layer chromatography and gas-liquid chromatography, and characterized by infrared spectroscopy and gas-liquid chromatography-mass spectrometry. Three groups of esters were identified as natural derivatives of acetic acid, acetoacetic acid, and 3-hydroxybutyric acid. The major ester fraction was identified as a mixture of C26 (10%), C27 (5%), and C28 (85%) oxoalcohol esters of acetoacetic acid. The major homolog consisted of equal amounts of 11-oxooctacosanyl 3-oxobutanoate and 12-oxooctacosanyl 3-oxobutanoate. Lesser amounts of 11- and 12-oxooctacosanyl and n-octacosanyl esters of acetic and 3-hydroxybutyric acids were also identified. The chain length distributions of these C26, C27, and C28 oxoalcohol and n-primary alcohol ester moieties, as well as the isomeric ratios for the 11- and 12-oxoalcohol isomers, were similar to the oxoaldehydes and unesterified oxoalcohols previously identified by Buckner et al (Buckner, J. S., Nelson, D. R., Haak, H., and Pomonis, J. G. (1984) J. Biol. Chem. 259, 8452-8470) as lipid components of the surface wax of M. sexta pupae.

Acetates↗
PubMed1985

Rat acetoacetic acid decarboxylase inhibition by acetone.

Although in mammals, acetone formation from acetoacetic acid is normally regarded as a non-enzymatic (spontaneous) process, the existence of an acetoacetic acid decarboxylase activity was postulated recently. The results imply that this enzymatic activity can be relatively important at the physiological concentrations of ketone bodies found in the rat and that acetone acts as a competitive inhibitor of this enzyme.

Acetone↗
PubMed1996

Mechanism of the reaction catalyzed by acetoacetate decarboxylase. Importance of lysine 116 in determining the pKa of active-site lysine 115.

Acetoacetate decarboxylase from Clostridium acetobutylicum (AAD) catalyzes the decarboxylation of acetoacetate via a Schiff base intermediate [Hamilton, G. A., & Westheimer, F. H. (1959) J. Am. Chem. Soc. 81, 6332; Fridovich, I., & Westheimer F. H. (1962) J. Am. Chem. Soc. 84, 3208]. The pKa of the active-site lysine (Lys 115) is 6.0, 4.5 pKa units less than the pKa of lysine in solution [Kokesh, F. C., & Westheimer, F. H. (1971) J. Am. Chem. Soc. 93, 7270; Frey, P. A., Kokesh, F. C., & Westheimer, F. H. (1971) J. Am. Chem. Soc. 93, 7266; Schmidt, D. E., Jr., & Westheimer, F. H. (1971) Biochemistry 10, 1249]. Westheimer and co-workers hypothesized that the pKa of Lys 115 is decreased by its spatial proximity to the epsilon-ammonium group of Lys 116. We have investigated this proposal by studying site-directed mutants of Lys 115 and Lys 116. Two substitutions for Lys 115 (K115C and K115Q) were both catalytically inactive at pH 5.95, the pH optimum of wild type AAD, demonstrating the importance of this residue in catalysis. Activity could be restored to K115C by aminoethylation with 2-bromoethyl-ammonium bromide (2-BEAB). Substitutions for Lys 116 (K116C, K116N, and K116R) had reduced but significant activities at pH 5.95. The effects of Lys 116 on the pKa of Lys 115 in the mutant AADs were evaluated following imine formation with 5-nitrosalicylaldehyde and reduction with NaBH4. Whereas the pKa of Lys 115 in K116R is similar to that observed for wild type AAD, the pKaS of Lys 115 in K116C and K116N were elevated to > 9.2. Alkylation of Cys 116 in K116C with 2-BEAB resulted in both significant activation and restoration of the pKa of Lys 115 to 5.9. These data support Westheimer's hypothesis that the pKa of the Schiff base-forming Lys 115 is decreased by its spatial proximity to the epsilon-ammonium group of Lys 116.

Amino Acid Sequence↗
PubMed1986

Rat acetoacetate decarboxylase: its role in the disposal of 4C-ketone bodies by the fetus.

21-day pregnant rats show high tissular and plasmatic acetone concentrations when submitted to a 48-hr fast. This rise is, in fact, associated with an enhanced placental and fetal acetoacetate decarboxylase activity. We propose that acetone formation by the fetus could be a mechanism for pH maintenance and that acetoacetate decarboxylase can play a significant role in the handling of 4C-ketone bodies under conditions in which the substrate concentration cannot easily be controlled by other physiological mechanisms.

Acetone↗
PubMed1976

[Behavior of some parameters of lipid and energy metabolism. 1. Behavior of the stationary concentrations of acetyl CoA, acetoacetate and adenosine phosphates in liver, as well as oxygen consumption and P/O ratios in liver homogenates of growing rats on diets differing in fat content].

Young rats were maintained on diets differing in fat content. The determination of certain parameters of the lipid and the energy metabolism in the liver showed that a high-fat diet resulted in a reduction of the stationary level of acetyl CoA, an increase in the concentration of acetoacetate and a reduction of the adenosine triphosphate content and the so-called energy charge. In case of intact respiratory chain phosphorylation, the oxygen consumption of the respective liver homogenates was simultaneously increased. The results obtained with a high-fat diet are indicative of the attainment of a metabolic state which seems to be typical of metabolic regulations in growing rats subjected to anabolic lipometabolism.

Acetoacetates↗
PubMed2006

Acetoacetate protects neuronal cells from oxidative glutamate toxicity.

Glutamate cytotoxicity contributes to neuronal degeneration in many central nervous system (CNS) diseases, such as epilepsy and ischemia. We previously reported that a high-fat and low-carbohydrate diet, the ketogenic diet (KD), protects against kainic acid-induced hippocampal cell death in mice. We hypothesized based on these findings that ketosis resulting from KD might inhibit glutamate cytotoxicity, resulting in inhibition of hippocampal neuronal cell death. Therefore, we investigated the role of ketone bodies [acetoacetate (AA) and beta-hydroxybutyrate (beta-OHB)] both in a mouse hippocampal cell line (HT22) and in rat primary hippocampal neurons. As a result, we found that pretreatment with 5 mM lithium AA and 4 mM Na beta-OHB protected the HT22 hippocampal cell line and primary hippocampal neuronal culture against 5 mM glutamate toxicity and that up to 2 hr of pretreatment with 5 mM AA had a protective effect against 5 mM glutamate toxicity in the HT22 cell line. Pretreatment with 5 mM AA decreased ROS production of HT22 cell line at 2 and 8 hr exposure of glutamate, and it decreased the appearance of annexin V-positive HT22 cells, which are indicative of an early stage of apoptosis, and propidium iodide-positive HT22 cells, which are indicative of necrosis.

Acetoacetates↗
PubMed1996

Carbon dioxide catalysis of the reaction of peroxynitrite with ethyl acetoacetate: an example of aliphatic nitration by peroxynitrite.

The reaction of peroxynitrite anion (O=N-OO-) with CO2 results in the formation of an unstable nitrosoperoxycarbonate anion adduct, O=N-OOCO-2 (1). Adduct 1 can serve as a source for several reactive intermediates, including the nitrocarbonate anion (O2N-OCO-2), the carbonate radical ion/nitrogen dioxide radical pair, and the nitronium ion/carbonate ion pair. One or more of these reactive intermediates mediate(s) electrophilic nitrations, for example of tyrosine residues in proteins, which is often observed in peroxynitrite-producing systems. We here report, for the first time, the nitration of an aliphatic substrate, ethyl acetoacetate, by peroxynitrite. The yield of nitration is markedly enhanced in the presence of added carbonate. The major product of this reaction is ethyl 2-nitroacetoacetate. The importance of this reaction is discussed in relation to the possible aliphatic nitrations of amines, sugars, thiols, and thioethers in peroxynitrite-producing biological systems.

Acetoacetates↗
PubMed1989

Positron emission tomographical studies of 1-11C-acetoacetate, 2-18F-fluoro-deoxy-D-glucose, and L-1-11C-tyrosine uptake by cat brain with an experimental lesion.

In cat brain with a freezing injury, the uptake of 1-11C-acetoacetate (11C-ACAC), 2-18F-fluorodeoxy-D-glucose (18FDG), and L-1-11C-tyrosine (11C-TYR) was monitored by positron emission tomography following intravenous administration of the tracers, at 1 day, and 1-3 weeks after the injury. The development and further course of the cold-induced oedema was monitored by magnetic resonance imaging. In the fresh (1 day old) lesion there was increased uptake of 11C-ACAC, probably due to release of the restrictive influence of the blood-brain barrier upon passage of the substance into brain. The uptake of 18FDG, which normally occurs by carrier-mediated transport at the barrier, was decreased in the fresh lesion, probably as a result of damage of the carrier mechanism. In the 3 week old lesion 18FDG uptake was still reduced, and 11C-ACAC uptake was still increased, although barrier function to Evans blue had recovered. It is suggested, that the increased 11C-ACAC uptake in the chronic lesion bears upon the proliferation of macrophages and reactive glial cells in the lesion. This is supported by the increased uptake of 11C-TYR in the 2 weeks old lesion, while in the fresh lesion 11C-TYR uptake was unchanged.

Acetoacetates↗
PubMed1984

Pathways of acetyl CoA production for lipogenesis from acetoacetate, beta-hydroxybutyrate, pyruvate and glucose in neonatal rat lung.

The rate of fatty acid synthesis from acetoacetate (AcAc) is 2-3 times greater than from glucose in developing rat lung. To determine the reason for this difference, we investigated the pathways of lipogenesis from [3-14C] AcAc, [3-14C] beta-hydroxybutyrate (beta OHB), [U-14C] glucose or [2-14C] pyruvate in minced lung tissue of 3- to 4-day-old rats. The addition of (-)hydroxycitrate, an inhibitor of ATP-citrate lyase, inhibited fatty acid synthesis from glucose, pyruvate, and beta OHB by 88%, 70% and 60%, respectively, but had no effect on that from AcAc. Benzene 1,2,3-tricarboxylate, an inhibitor of tricarboxylate translocase, inhibited fatty acid synthesis from all substrates by at least 50%. Incubation with aminooxyacetate, an inhibitor of aspartate aminotransferase, had no effect on lipid synthesis from glucose, pyruvate or AcAc, but increased lipid synthesis from beta OHB. Results indicate that for lipid synthesis in the neonatal lung, acetyl CoA from AcAc is derived predominantly from a cytoplasmic pathway involving AcAcCoA synthetase and AcAcCoA thiolase, whereas citrate is the major route of acetyl group transfer from glucose. Lipogenesis from beta OHB involves both the cytoplasmic and citrate pathways.

3-Hydroxybutyric Acid↗
PubMed1983

Lung lipid synthesis from acetoacetate and glucose in developing rats in vitro.

Acetoacetate (AcAc) and glucose were compared as energy sources and as precursors for lipid synthesis in the lungs of developing rats. Minced lung tissue was incubated with [3-14C]AcAc or [U-14C]glucose and the oxidation of each substrate to CO2 or its incorporation into tissue lipids was quantified. The highest rates of oxidation were obtained during the first 5 days for AcAc and the first 2 days of life for glucose and oxidation of AcAc was 3-4 times greater than that of glucose at all ages. Throughout postnatal development, the rates of nonsaponifiable lipid, fatty acid and hence total lipid (chloroform/methanol extractable) synthesis from AcAc were 2-3 times those of glucose. The highest rates of total lipid synthesis from AcAc and glucose were observed at birth. Glucose was utilized for glyceride-glycerol synthesis at a higher rate than AcAc. Similar patterns of incorporation of AcAc and glucose into various lipid classes were noted. Of the total lipids synthesized from AcAc and glucose, respectively, phospholipid plus monoglyceride accounted for 64% and 77%, triglyceride 13% and 13%, diglyceride plus cholesterol 11% and 4%, fatty acids 9% and 4%, and cholesteryl esters 3% and 1%. AT birth, the specific activities of all lipids except triglyceride derived from AcAc were greater than those from glucose. Rates of synthesis of all complex lipids declined with age. The results of these experiments demonstrate that AcAc is utilized more readily than glucose for energy production and lipid synthesis in developing rat lungs.

Acetoacetates↗