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PubMed1976

Lipogenesis from ketone bodies in rat brain. Evidence for conversion of acetoacetate into acetyl-coenzyme A in the cytosol.

The metabolism of acetoacetate via a proposed cytosolic pathway in brain of 1-week-old rats was investigated. (-)-Hydroxycitrate, an inhibitor of ATP citrate lyase, markedly inhibited the incorporation of carbon from labelled glucose and 3-hydroxybutyrate into cerebral lipids, but had no effect on the incorporation of labelled acetate and acetoacetate into brain lipids. Similarly, n-butylmalonate and benzene-1,2,3-tricarboxylate inhibited the incorporation of labelled 3-hydroxybutyrate but not of acetoacetate into cerebral lipids. These inhibitors had no effect on the oxidation to 14CO2 of the labelled substrates used. (-)-Hydroxycitrate decreased the incorporation of 3H from 3H2O into cerebral lipids by slices metabolizing either glucose or 3-hydroxybutyrate, but not in the presence of acetoacetate. (-)-Hydroxycitrate also differentially inhibited the incorporation of [2-14C]-leucine and [U-14C]leucine into cerebral lipids. The data show that, although the acetyl moiety of acetyl-CoA generated in brain mitochondria is largely translocated as citrate from these organelles to the cytosol, a cytosolic pathway exists by which acetoacetate is converted directly into acetyl-COA in this cellular compartment.

Acetates↗
PubMed2004

Evaluation of a bedside blood ketone sensor: the effects of acidosis, hyperglycaemia and acetoacetate on sensor performance.

AIMS: To assess the performance of a handheld bedside ketone sensor in the face of likely metabolic disturbances in diabetic ketoacidosis, namely: pH, glucose and acetoacetate. METHODS: The effects of pH (7.44-6.83), glucose (5-50 mmol/l) and acetoacetate (0-5 mmol/l) were examined in venous blood to investigate the accuracy of betahydroxybutyrate measurement (0-5 mmol/l) by a handheld ketone sensor. Sensor results were compared with a reference method. Linear regression models were fitted to the difference between the methods with the concentration of metabolite as the explanatory factor. RESULTS: Decreasing pH and increasing glucose had no effect on the accuracy of the handheld ketone sensor; the gradients of the fitted lines were -0.14 and -0.003, respectively. The 95% confidence intervals were -0.7-0.4 and -0.01-0.004, respectively (P = 0.59 and 0.4, respectively). In the acetoacetate study, a positive relationship between the sensor and reference method results was found, the gradient was 0.09. The 95% confidence interval was 0.05-0.14 (P < or = 0.001), indicating that high concentrations of acetoacetate interfere with the sensor performance. CONCLUSIONS: Acidosis and hyperglycaemia have minimal effects on the sensor performance. However, high concentrations of acetoacetate result in some overestimation of betahydroxybutyrate. This bedside ketone sensor provides useful data over a broad range of conditions likely to be encountered during moderate to severe diabetic ketoacidosis.

Acetoacetates↗
PubMed1986

Acetoacetate and glucose as lipid precursors and energy substrates in primary cultures of astrocytes and neurons from mouse cerebral cortex.

Primary cultures of astrocytes and neurons derived from neonatal and embryonic mouse cerebral cortex, respectively, were incubated with [3-14C]acetoacetate or [2-14C]glucose. The utilization of glucose and acetoacetate, the production of lactate, D-3-hydroxybutyrate, and 14CO2, and the incorporation of 14C and of 3H from 3H2O into lipids and lipid fractions were measured. Both cell types used acetoacetate as an energy substrate and as a lipid precursor; lactate was the major product of glucose metabolism. About 60% of the acetoacetate that was utilized by neurons was oxidized to CO2, whereas this was only approximately 20% in the case of cultured astrocytes. This indicates that the rate at which 14C-labeled Krebs cycle intermediates exchange with pools of unlabeled intermediates is much higher in astrocytes than in neurons. Acetoacetate is a better precursor for the synthesis of fatty acids and cholesterol than glucose, presumably because it can be used directly in the cytosol for these processes; preferential incorporation into cholesterol was not observed in these in vitro systems. We conclude that ketone bodies can be metabolized both by the glial cells and by the neuronal cells of developing mouse brain.

3-Hydroxybutyric Acid↗
PubMed1991

Pyruvate carboxylation prevents the decline in contractile function of rat hearts oxidizing acetoacetate.

Acetoacetate, when present as the only fuel for respiration in rat hearts, causes an impairment in contractile function that is reversible with the addition of substrates that can contribute to anaplerosis. To determine the importance of pyruvate carboxylation via NADP(+)-dependent malic enzyme on metabolism and function in hearts oxidizing acetoacetate, isolated working rat hearts were perfused with [1-14C]pyruvate and acetoacetate. While the cardiac power output after 60 min of perfusion in hearts utilizing acetoacetate alone had fallen to 44% of the initial value, the addition of pyruvate resulted in a stable performance with no fall in the work output. When hydroxymalonate, an inhibitor of NADP(+)-dependent malic enzyme and malate dehydrogenase, was added to the two substrates, function at 60 min was similar to the value for hearts oxidizing acetoacetate alone. Measurements of the specific activities of malate, aspartate, and citrate confirm inhibition of both pyruvate carboxylation and malate oxidation. The findings are consistent with a mechanism in which the enrichment of malate by pyruvate improves function by increasing the production of reducing equivalents by the malate dehydrogenase and the isocitrate dehydrogenase reactions increase flux through the span of the tricarboxylic acid cycle from malate to 2-oxoglutarate. The present study demonstrates the physiological importance of anaplerotic pathways in maintaining contractile function in the heart.

Acetoacetates↗
PubMed1990

An enzymatic assay method for D(-)-3-hydroxybutyrate and acetoacetate involving acetoacetyl coenzyme A synthetase from Zoogloea ramigera.

An enzyme assay method for D(-)-3-hydroxybutyrate and acetoacetate involving acetoacetyl coenzyme A (CoA) synthetase was developed. To determine the concentration of D-3-hydroxybutyrate, it was oxidized with D-3-hydroxybutyrate dehydrogenase in the presence of nicotinamide adenine dinucleotide (NAD+) to acetoacetate, which was then converted to acetyl CoA via acetoacetyl CoA through the combined actions of acetoacetyl CoA synthetase and 3-ketothiolase in the presence of adenosine triphosphate (ATP) and CoA. To determine the concentration of acetoacetate, acetoacetyl CoA generated from acetoacetate with acetoacetyl CoA synthetase was reduced to 3-hydroxybutyryl CoA with 3-hydroxyacyl CoA dehydrogenase in the presence of NADH. The amount of D-3-hydroxybutyrate or acetoacetate was estimated from the increase or decrease in the absorbance at 340 nm, respectively. The present assay method seemed to be accurate and quick. Furthermore, as to the assaying of D-3-hydroxybutyrate, the omission of hydrazine, which is included for the standard method, may be preferable for routine assaying.

3-Hydroxybutyric Acid↗
PubMed2002

Polyunsaturated fatty acids and acetoacetate downregulate the expression of the ATP-binding cassette transporter A1.

Low HDL cholesterol is a frequent cardiovascular risk factor in diabetes. Because of its pivotal role for the regulation of HDL plasma levels, we investigated in vivo and in vitro regulation of the ATP-binding cassette transporter A1 (ABCA1) by insulin and metabolites accumulating in diabetes. Compared with euglycemic control mice, ABCA1 gene expression was severely decreased in the liver and peritoneal macrophages of diabetic mice. Treatment with insulin restored this deficit. Incubation of cultivated HepG2 hepatocytes and RAW264.7 macrophages with unsaturated fatty acids or acetoacetate, but not with insulin, glucose, saturated fatty acids, or hydroxybutyrate, downregulated ABCA1 mRNA and protein. The suppressive effect of unsaturated fatty acids and acetoacetate became most obvious in cells stimulated with oxysterols or retinoic acid but was independent of the expression of the thereby regulated transcription factors liver-X-receptor alpha (LXRalpha) and retinoid-X-receptor alpha (RXRalpha), respectively. Unsaturated fatty acids and acetoacetate also reduced ABCA1 promotor activity in RAW264.7 macrophages that were transfected with a 968-bp ABCA1 promotor/luciferase gene construct. As the functional consequence, unsaturated fatty acids and acetoacetate inhibited cholesterol efflux from macrophages. Downregulation of ABCA1 by unsaturated fatty acids and acetoacetate may contribute to low HDL cholesterol and increased cardiovascular risk of diabetic patients.

Acetoacetates↗
PubMed1986

Effect of hypoxia and short-term fasting on the plasma acetoacetic acid level in rats of different ages.

The acetoacetic acid level in rat plasma was studied by Walker's method (Walker 1954) during ontogenesis, after 20 min exposure to altitude hypoxia (7,000 or 9,000 m) or after short-term (24 h) deprivation of food and water. Wistar rats of both sexes, bred at the authors' department, were employed. The results confirmed earlier findings on the acetoacetic acid level during ontogenesis (Drahota et al. 1963) in addition, it was found that the level of the given acid in the rats' blood fell steadily during the whole of the pre-weaning period. Short-term deprivation of food and water significantly raised the plasma acetoacetic acid level in 5- and 10-day-old and adult rats; the maximum absolute increase was found in the youngest age groups. Hypoxia corresponding to 7,000 m significantly raised the plasma acetoacetic acid level in 5- and 10-day-old rats, but not in adult animals. Hypoxia corresponding to 9,000 m raised it significantly in 5-day-old animals only. We associate these findings with the possible utilization of acetoacetic acid, as a suitable energy substrate, by certain tissues, in particular the tissues of the CNS, in the youngest organisms.

Acetoacetates↗
PubMed1984

Biosynthesis of phospholipids and sphingolipids from acetoacetate and glucose in different regions of developing brain in vivo.

The incorporation of 14C-label from subcutaneously injected [3-14C]acetoacetate and [U-14C]glucose into phospholipids and sphingolipids in different regions of developing rat brain was determined. In all regions, phosphatidylcholine was the lipid synthesized most readily from either substrate. The percentages of radioactivity in other phospholipids and most sphingolipids remained relatively constant throughout postnatal development. An exceptional increase in the percentage of radioactivity incorporated into cerebroside, coinciding with a decrease of incorporation into phosphatidylcholine, was first noted on day 12 and continued until a maximal level was reached between days 18 and 20 of postnatal age. These developmental changes in preferential synthesis of lipids were associated with increased demands for phospholipids and cerebroside during the early and late postnatal stages, respectively. There was no difference in accumulation of radioactivity from acetoacetate, expressed as dpm of [14C]acetoacetate recovered in phospholipids plus sphingolipids per g of tissue, among all brain regions during the first 5 days of life. During active myelination (12 to 20 days of age); however, the amount of 14C-label was highest in brain stem, ranging from 1.9- to 2.3-fold greater than values for cerebrum and thalamus. The region with the next highest accumulation was cerebellum, followed by midbrain. During the same period, brain stem was likewise the most active site of accumulation of radioactivity from 14C-labeled glucose. Higher amounts of [14C]acetoacetate label accumulated in lipids of brain stem and cerebellum, relative to midbrain, thalamus, and cerebrum, coincide with evidence that active myelination begins in the hindbrain and proceeds rostrally toward the forebrain. Ketone bodies could therefore serve as a potential source of phospholipids and sphingolipids for brain growth and maturation.

Acetoacetates↗
PubMed1982

Biosynthesis of lung lipids from acetoacetate and glucose in the developing rat in vivo.

1. [3-14C]Acetoacetate and [U-14C]glucose administered to rats were readily utilized for synthesis of phospholipids, cholesterol and glycerides in the lung during suckling period. 2. Among all lipids synthesized, phosphatidylcholine accounted for 31-48% from [14C]acetoacetate and 30-46% from [14C]glucose. The synthesized phosphatidylcholine contained predominantly [14C]-labeled palmitate. 3. Glycerol lipids represented 83-92% and 56-68% of total lipids synthesized from [14C]glucose and [14C]acetoacetate, respectively. 4. Glucose is the preferred substrate for glyceride-glycerol, while acetoacetate appears better for fatty acid and cholesterol synthesis.

Acetoacetates↗
PubMed1992

A 28-day feeding study with ethyl acetoacetate in rats.

Ethyl acetoacetate encapsulated in gum arabic was administered in rodent diet for a minimum of 28 consecutive days to groups of 16 male and 16 female rats (Sprague-Dawley strain) at levels of approximately 100, 300 and 1000 mg/kg body weight/day. A further group of 16 male and 16 female rats was given rodent diet containing gum arabic as a control. The administration of ethyl acetoacetate in the diet did not adversely affect the growth or general health of the animals or their food intakes. None of the minor variations observed in the haematology, serum chemical analyses or urine analyses are considered to be indicative of a treatment-related toxic effect. Caecal enlargement was seen in male rats treated with the top dose of ethyl acetoacetate, but this was accompanied by a normal histopathology. Few histopathological abnormalities were observed. Proteinaceous casts were found in the bladder of approximately half the male rats given 1000 mg ethyl acetoacetate/kg, and nephrocalcinosis was a common occurrence in female rats in this dose group. Renal function was unimpaired in treated male and female rats, and the histopathological findings are common in the strain of rats chosen for this study. Although the caecal enlargement and the changes in kidney and bladder of rats given 1000 mg ethyl acetoacetate/kg are noted, it is considered that ethyl acetoacetate did not produce treatment-related adverse effects in rats during this study.

Acetoacetates↗
PubMed1980

Prevention of maleate-induced tubular dysfunction by acetoacetate.

Maleate administration produces features that closely resemble the Fanconi syndrome. To determine whether this dysfunction is caused by maleate or its metabolite, maleyl-CoA, which is produced in the succinyl-CoA transferase reaction, the effect of pretreatment with acetoacetate on the maleate dysfunction was tested in rats, Infusion of acetoacetate, 90 mu mol . min-1 . kg body wt-1 protects the kidney from maleate action, whereas administration of propionate, a monocarboxylic anion and CoA-dependent metabolite resembling the anion of acetoacetate, has no effect on maleate-induced renal dysfunction. Maleate (100 mg/kg body wt) alone lowered kidney ATP concentration by 44%, whereas maleate with acetoacetate did not prevent the decreased renal ATP (42%), while glucosuria, phosphaturia, calciuria, and bicarbonaturia were significantly diminished. Similar changes in renal ATP level were observed in rats treated with propionate or propionate and maleate in combination. These experiments demonstrate that maleate per se is not inhibitory but that its metabolite, presumably maleyl-CoA, may inhibit tubule function.

Acetoacetates↗
PubMed2003

Osmotonicity of acetoacetate: possible implications for cerebral edema in diabetic ketoacidosis.

BACKGROUND: Rapid drops in blood glucose and sodium levels during treatment of diabetic ketoacidosis (DKA) can cause a drop in the osmotonicity of plasma, resulting in cerebral edema. Ketone bodies are assumed to move freely in and out of cells, so it is assumed that they do not contribute to the tonicity of plasma or influence fluid shifts. The assumption that ketone bodies do not contribute to osmotonicity has not been tested previously. The experiment described here was done to check if acetoacetate has osmotonicity. MATERIAL/METHODS: A modified erythrocyte fragility test was used to check the osmotonic and osmoprotective effects of the ketone body. Red blood cells were suspended in different test tubes containing distilled water, normal saline, glucose, urea and acetoacetic acid (lithium salt C4H5O3Li). All solutions (except the tube with distilled water) were made to match the osmolality of plasma. We hypothesized that solutions in which red cell hemolysis does not take place have greater tonicity than the tonicity of 0.45% saline. RESULTS: Spectrophotometry showed that there was no hemolysis in the solutions of normal saline or solutions containing glucose or acetoacetate. Complete hemolysis was demonstrated in the tube with plain distilled water and also in the solutions containing urea. CONCLUSIONS: This study shows that acetoacetate is functionally similar to glucose in that it contributes to increased osmotonicity. The drop in ketone body levels can produce a drop in the osmolar tonicity of plasma and precipitate cerebral edema.

Acetoacetates↗
PubMed1977

A kinetic spectrophotometric assay for rapid determination of acetoacetate in blood.

We describe an automated kinetic assay for acetoacetate in blood. Acetoacetate is enzymatically reduced to D-beta-hydroxybutyrate and the reaction is monitored for 60 s with a reaction-rate analyzer. This technique allows low concentrations of acetoacetate to be measured with good precision and overcomes many of the problems associated with other automated techniques. Our studies on the stability of acetoacetate emphasize the need for care in handling specimens. The use of a reaction-rate analyzer, an item of equipment common to most laboratories, allows for rapid handling of samples in small or large batches, depending on the needs of the laboratory.

Acetoacetates↗
PubMed1984

Role of acetoacetyl-CoA synthetase in acetoacetate utilization by tumor cells.

Tumors of peripheral tissues contain low levels of succinyl CoA-acetoacetate CoA transferase activity which is not induced in vitro by prolonged cultivation in 2.5 mM DL-3-hydroxybutyrate. Although this enzyme is considered to be the main agent controlling the extent to which ketone bodies serve as metabolic substrates such tumors metabolize D(-)-3-hydroxy[3(14)C]butyrate to 14CO2. Also addition of 3-hydroxybutyrate and/or acetoacetate reduces the amount of 14CO2 produced from D-[U-14C] glucose suggesting a common metabolic intermediate. These observations can be accounted for by the presence of acetoacetyl-CoA synthetase, an enzyme which is able to synthesize acetoacetyl-CoA directly from acetoacetate, ATP and coenzyme A. This is the first demonstration of this enzyme in tumor tissue. The rate of metabolism of acetoacetate by this enzyme is sufficient to account for the production of CO2 from 3-hydroxybutyrate.

3-Hydroxybutyric Acid↗
PubMed1976

Mammalian acetoacetate decarboxylase activity. Its distribution in subfractions of human albumin and occurrence in various tissues of the rat.

In this article further information is presented about the characteristics of the mammalian enzyme acetoacetate decarboxylase (acetoacetate carboxylase, EC 4.1.1.4). The Michaelis-Menten plot shows a sigmoidal relationship between the enzyme activity (v) and the substrate concentration (s) indicating an allosteric hindrance. Because of this, the KM value can only be predicted to be equal to or less than 1 X 10(-1) M. Cysteine and glutathione, although activating the spontaneous decarboxylation, have no effect upon the enzyme activity. From experiments with human albumin by means of gel filtration with Sephadex G-200, it can be concluded that the acetoacetate decarboxylase activity does not depend upon the degree of polymerisation of albumin. From experiments performed by means of ion exchange chromatography the enzyme activity may be localized in the non-mercaptalbumin fraction. Investigation of enzyme activity in homogenates of various rat tissues, as well as in their respective subfractions, reveals that: (1) the specific activity of brain tissue exceeds those of liver and kidney and (2) most of the activity in liver tissue is localized in the 20 000 X g supernatant, containing the endoplasmatic reticulum, the ribosomes and the soluble part of the cytoplasm, while in brain tissue a high activity is found in the nuclei fraction.

Acetoacetates↗
PubMed1983

Acetoacetate: a major substrate for the synthesis of cholesterol and fatty acids by isolated rat hepatocytes.

Evidence is presented that isolated, intact rat hepatocytes can synthesize fatty acids and cholesterol from acetoacetate. The quantitative importance of these processes is evaluated by measuring total rates of fatty acid and cholesterol synthesis by incorporation of 3H from 3H2O. The contribution of acetoacetate varies from 14-54% and from 21-75% for de novo synthesized fatty acids and cholesterol, respectively, depending on the physiological condition of the donor rat. The relative contribution of acetoacetate to cholesterol synthesis is 1.4-2.3-times greater than to fatty acid synthesis.

Acetoacetates↗
PubMed1989

Determination of acetoacetate in urine by solid-phase spectrophotometry.

A method for the determination of acetoacetate has been developed based on solid-phase spectrophotometry (SPS). The acetoacetate reacts with nitroprusside and glycine and the reaction product is sorbed on Dowex 1-X8 resin. The absorbance of the resin phase at 590 and 720 nm is measured directly. The calibration graph is linear up to 3.3 mg l-1 and the RSD is 1.9%. The detection limit is 7.6 micrograms l-1. The method has been applied to the determination of acetoacetate in normal and diabetic subjects' urine without pretreatment of the samples, and the results compared with those of 1H-NMR and homogeneous nitroprusside methods.

Acetoacetates↗
PubMed1990

An improved synthesis of carbon-11 labeled acetoacetic acid and an evaluation of its potential for the investigation of cerebral pathology by positron emission tomography.

1-11C-acetoacetic acid was synthesized by carboxylation of the acetone carbanion. Purification was carried out using HPLC. The product was obtained with a radiochemical yield of up to 58%, corrected for decay, in a total preparation time of 30 min. The distribution of 1-11C-acetoacetic acid after injection into adult Wistar rats and cats was investigated by PET. When the tracer was injected into cats, 3 weeks after inflicting a unilateral freezing lesion upon the brain, accumulation of 1-11C-acetoacetic acid in the ipsilateral brain hemisphere was observed.

Acetoacetates↗