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PubMed1996

Ketone body ratios of the superior and inferior vena cava and of pulmonary arterial blood compared to that of arterial blood: central venous ketone body ratio as a substitute for the arterial ketone body ratio.

To investigate the ketone body ratio (acetoacetate/3-hydroxybutyrate) of central venous blood compared to that of peripheral arterial blood, the acetoacetate and 3-hydroxybutyrate concentrations in paired peripheral arterial and central venous or pulmonary arterial blood were measured. The ketone body concentrations in superior and inferior vena cava blood were significantly (P < 0.0001) lower than those in peripheral arterial blood, whereas those in pulmonary arterial blood were almost the same as those in peripheral arterial blood. These results indicate that ketone bodies were metabolized in the muscles, which reduced their levels in vena cava blood, but ketone bodies newly produced by the liver were transported to the right side of the heart via the hepatic vein, giving concentrations in pulmonary arterial blood that were almost the same as those in peripheral arterial blood. On the other hand, the correlation coefficients (r2) of the arterial blood ketone body ratio to the ratio of superior and inferior vena cava and pulmonary arterial blood were 0.897, 0.767 and 0.882, respectively. The ratios of central venous ketone body ratio/arterial blood ketone body ratio were 0.89 +/- 0.15 in the superior vena cava, 0.64 +/- 0.18 in the inferior vena cava and 1.01 +/- 0.15 in the pulmonary artery.

3-Hydroxybutyric Acid↗

PubMed1996

Monte Carlo spreadsheet modeling of stable isotope biosynthesis.

Metabolic physiologists often introduce stable isotopes, atoms containing additional neutrons, into molecules during biosynthesis. This tags the newly synthesized material by altering its mass. Monte Carlo analysis is implemented on a popular spreadsheet to analyze this process. An example is provided where acetoacetate is synthesized by condensation of two acetate moieties. The precursor acetate is present as a mixture of natural, and 13C enriched, acetate. Monte Carlo spreadsheet modeling captures the complexity of the multi-species isotope biosynthesis by repetitively performing multiple simultaneous Boolean calculations. The effects of increasing the number of molecules synthesized on the goodness of fit of between model and an exact analytical solution is illustrated.

Acetoacetates↗

PubMed1989

Isolated colonocyte metabolism of glucose, glutamine, n-butyrate, and beta-hydroxybutyrate in malnutrition.

The colonic mucosa may be especially vulnerable during starvation and malnutrition, as luminal nutrients make the greatest contribution to its energy production. To investigate possible metabolic changes in the colonic mucosa during nutrient restriction, we studied substrate utilization by colonocytes isolated from three groups of 6-wk-old rats: control, fasted (72 h), and chronically malnourished animals. Isolated colonocytes were incubated with nonlabeled and 14C-labeled substrates (glucose, glutamine, n-butyrate, or beta-hydroxybutyrate). Substrate oxidation and net increase of intermediary metabolites were reduced in fasted and malnourished animals. The effect of fasting on substrate oxidation was greater than that of chronic malnutrition for all substrates tested except n-butyrate. The total ketone body concentrations and beta-hydroxybutyrate to acetoacetate ratios were higher in the fasted and malnourished groups than in controls. The findings suggest that the colonic mucosa responds to nutrient deprivation by a general reduction of oxidative metabolism that is associated with an altered redox state.

3-Hydroxybutyric Acid↗

PubMed1986

Evaluation of a short-time, oxygen carrier-free perfusion model in rat liver: mitochondrial energy metabolism and insulin effect.

Livers of rats fasted for 18 hr were perfused for 60 min at 37, 35, and 32 degrees C in a simple noncirculating system with a carbogen (95%, 5% CO2) equilibrated, oxygen carrier-free, glucose-containing (200 mg X dl-1) cristalloid perfusate (pH 7.4, 280 mosmol X kg-1) without or with the addition of insulin (10 U X hr-1), and analyzed for tissue ATP, ADP, AMP, acetoacetate, and beta-hydroxybutyrate as well as for parameters of the energy metabolism of isolated mitochondria. Perfusion without insulin at 37 degrees C caused significant alterations: ATP and total adenine nucleotides (TAN) dropped to 62 and 74% of the control values (3.33 and 4.57 mumol X g-1), respectively. The energy charge potential ECP decreased from 0.842 to 0.713. Also, the mitochondrial phosphorylation rate (PR), the respiratory control ratio (RC), and the state 3 respiration rate (ST 3) were significantly depressed to 62, 54, and 72% of the control values. Perfusion with insulin maintained a normal metabolic pattern: ATP 105%, TAN 97%, ECP 0.877, PR 94%, RC 69%, and ST 3 105%. The metabolic deterioration during insulin-free perfusion was decreased at 35/32 degrees C: ATP 67/82%, PR 72/95%, RC 74/87%. At 35 degrees C, insulin ameliorated the metabolic pattern, but normal ranges were no longer reached. At 32 degrees C, insulin had no effect.

3-Hydroxybutyric Acid↗

PubMed1988

The influence of ketosis on the metabolic response to skeletal trauma.

Intravenous glucose and ketone body feeding were compared for their potential in altering urinary nitrogen losses by the traumatized rat. Eighteen male rats were traumatized by bilateral femoral fracture. The rats were fed totally by vein for 3 days prior and 3 days after injury and the infusion rate was held constant over the 6 days of infusion. Group GT rats were fed glucose as the source of nonprotein energy while group MT rats were fed a mixture of 72% monoacetoacetin (the monoglyceride of acetoacetate)-28% glucose for the nonprotein energy. Total urinary nitrogen excretion on a 24-hr basis was measured for each of the 6 days of intravenous feeding. On the third day post-trauma, each rat was evaluated for leucine kinetics using a continuous infusion of L-[1-14C]leucine and measurement of breath and plasma specific activities. Rats from group MT were hyperketonemic and normoglycemic and rats from group GT were normoketonemic and hyperglycemic. Urinary nitrogen losses, leucine oxidation, and leucine turnover were similar for the two groups. We conclude that ketone bodies are as good an intravenous source of energy as is glucose, and the ketone bodies do not cause hyperglycemia.

Acetoacetates↗

PubMed1992

Gut and liver coordinated metabolic response following major torso injury.

Major trauma provokes a stress response which is mediated, in part, via glucagon, catecholamines, and cortisol. These stress hormones modulate the choice of energy substrate for various tissues. While glucose and fatty acids are considered the preferred fuels, ketone bodies (26/ATP/mole) may be a viable alternative. In this study, we measured the concentrations of acetoacetate and beta-hydroxybutyrate (3-OHB) in the portal as well as systemic circulations of 10 critically injured patients (revised trauma score = 6.8 +/- 0.5, injury severity score = 27 +/- 3) during the first 5 postoperative days. At 6 hr postinjury, 3-OHB was elevated in the portal system (0.34 +/- 0.01 mM) while depressed systemically (0.09 +/- 0.02 mM), indicating that the gut was capable of ketogenesis. In contrast, at 24 hr, 3-OHB rose systemically (0.39 +/- 0.02 mM) while decreasing in portal blood (0.09 +/- 0.01 mM) implying gut ketone consumption. Moreover, the systemic ketone body ratio became elevated at 24 hr, suggesting an enhanced liver energy status. In summary, we believe ketogenesis is stimulated by major trauma. Initially, the gut supports ketone concentration in the systemic circulation, whereas, by 24 hr, the gut becomes a ketone consumer and the liver maintains circulating levels.

Abdominal Injuries↗

PubMed1986

Decreased ketonaemia in the monosodium glutamate-induced obese rats.

Plasma concentrations of total ketone bodies, acetoacetate (AcAc) and 3-hydroxybutyrate (3-OHBA) in monosodium glutamate (MSG)-induced obese rats were measured. MSG-treated rats showed higher Lee's indices, shorter naso-anal and tail length, and a more marked intraperitoneal fat deposition than control rats. Plasma concentrations of glucose, free fatty acid, triglyceride and phospholipids were significantly increased in the MSG-treated rats as compared to the control rats (24 weeks-old). Plasma levels of total ketone bodies, AcAc and 3-OHBA were all decreased in the MSG-treated rats as compared to control rats. The ratio, 3-OHBA/AcAc in the MSG-treated rats were not different from those in the control rats.

3-Hydroxybutyric Acid↗

PubMed1992

Mechanism of inhibitory action of ketone bodies on the production of reactive oxygen intermediates (ROIS) by polymorphonuclear leukocytes.

We determined an effect of acetoacetic acid (AcAc) and 3-hydroxybutyrate (3-OHB) on the production of reactive oxygen intermediates (ROIs) in polymorphonuclear leukocytes from healthy volunteers. Both AcAc and 3-OHB inhibited the luminol-dependent chemiluminescence (LDCL) activities assessed with initial slope and the inhibition rates were about 42%, 44% respectively by AcAc and 3-OHB when the leukocytes were preincubated with 10 mM AcAc or 3-OHB for 60 minutes. The LDCL activity was reduced by 16% and 42% following the addition of 1mM and 10 mM AcAc. The similar reduction of the LDCL activity was observed in the addition of 3-OHB. Either 3-OHB or AcAc failed to show a significant reduction of myeloperoxidase (MPO) activity. However, both 3-OHB and AcAc dose-dependently inhibited superoxide anion (O2-) production, measured by using cytochrome c. These data provided evidence that both 3-OHB and AcAc suppress neutrophil oxidative metabolism with respect with O2- production.

3-Hydroxybutyric Acid↗

PubMed1976

The effect of bacterial infections on ketone concentrations in rat liver and blood and on free fatty acid concentrations in rat blood.

The concentrations of cytoplasmic lactate and pyruvate and the NAD+/NADH ratio and the concentrations of mitochondrial acetoacetate, beta-hydroxybutyrate, and the NAD+/NADH ratio were determined in normal, fed, and fasted rats, and in rats infected with Streptococcus pneumoniae, Francisella tularensis, and Salmonella typhimurium. The various infections were found to have little or no effect on the cytoplasmic parameters. In normal rats, fasting caused a marked increase in blood and hepatic ketone concentration and in serum free fatty acid content. Fasted infected rats, however, did not show the increase in ketone bodies or serum free fatty acids normally associated with fasting alone. The mitochondrial NAD+/NADH ratio increased as the infections progressed, reversing the normal trend. The introduction of an infection during the fasting state when ketone bodies and serum free fatty acids were elevated caused a marked depression in their concentration. These data have led to a postulation of decreased lipolysis in the infected host to account for the lowered hepatic and blood ketone bodies and the decreased level of serum free fatty acids.

Acetoacetates↗

PubMed1980

Effect of portacaval shunt on circulating free fatty acids and ketone bodies in rats.

To ascertain whether portal diversion affects ketone body (KB) metabolism, fasting circulating levels of free fatty acids (FFA), acetoacetate (AcAc) and B-hydroxybutyrate (3-OH-B) were measured in portacaval shunted (PCS), sham-operated (S-O) and unoperated control (C) rats. In PCS animals blood KB concentration was clearly reduced when compared with S-O and C rats. Beta-hydroxybutyrate level was significantly lower in PCS rats, whereas AcAc concentration did not appear significantly modified in these animals. The hypothesis is proposed that hypoketonemia induced by portal diversion is due to reduced hepatic availability of fatty acids.

Acetoacetates↗

PubMed1982

A comparison of the uptake of 3-hydroxy-3-methyl-glutaric acid in newborn and adult rat kidney.

The developmental aspects of the renal uptake of 3-OH-3-CH3-glutaric acid (HMG) was examined using isolated renal tubules prepared from both newborn and adult rats and isolated renal brush border membranes vesicles from adult rats. The accumulation of 70 microM HMG by both newborn and adult tubules reached a steady state and achieved a distribution ratio (DR) of 4.9 and 6.5, respectively; decreased DR's at higher substrate concentrations suggest concentration-dependent uptake. Lineweaver-Burk analysis of the 5 min calculated velocities of HMG uptake by newborn and adult tubules indicate a single transport system with the same apparent Km of 0.2 mM in both age groups. The Vmax in adult rats was twofold greater than in newborn (0.95 versus 0.44 mM/1/5 min). The carrier system for HMG is assumed to be distinct from those of amino acids and sugars because tubule uptake of HMG is not affected by the presence of alpha-NH2-isobutyric acid and alpha-methyl-D-glucoside. Sodium maleate and acetoacetate significantly decreased HMG uptake in tubules of both age groups. HMG uptake by isolated renal brush border membrane vesicles from adult rats suggests that uptake is both carrier-mediated and Na+-dependent. These observations are consistent with renal tubular HMG uptake by an energy-dependent, carrier-mediated system.

Acetoacetates↗

PubMed1988

Glucose, glutamine, and ketone-body metabolism in human enterocytes.

Suspensions of metabolically viable human small-intestinal epithelial cells (enterocytes) were used to assess the metabolism of substrate(s) normally derived from the blood circulation to the intestinal mucosa (glucose, glutamine, and ketone bodies). Glutamine, glutamate, and glucose were the only substrates that caused major increases in oxygen consumption by isolated human enterocytes. In human enterocytes 72% of glucose could be accounted for as lactate. Human enterocytes utilized glutamine at about 14.90 mumol/min/g dry wt, with glutamate, alanine, aspartate, and ammonia as the major end-products. Human enterocytes utilized 3-hydroxybutyrate and acetoacetate at similar rates. Under the experimental condition employed, the respiratory fuels of human enterocytes include glutamine, glucose, and to a lesser extent, ketone bodies as indicated in the proportion of oxygen consumption attributed to these fuels and to the extent of utilization.

Acetoacetates↗

PubMed1985

Ketone kinetics and D-(-)-3-hydroxybutyrate-induced inhibition of feeding in rats.

For further investigation of the mechanism involved in D,L-3 hydroxybutyrate (DL3HB)-induced inhibition of feeding [5], we measured cumulative food intake following subcutaneous injections of DL3HB or D-(-)-3-hydroxybutyrate (D3HB), and plasma ketone levels following subcutaneous injections of D3HB or acetoacetate (ACAC) in rats. Subcutaneously injected DL3HB (10 mmoles/kg body weight) and D3HB (5 mmoles/kg body weight) reduced food intake a similar amount. After injection of D3HB or ACAC (5 mmoles/kg body weight) plasma concentrations of the injected ketone bodies reached a similar high level at 20 min and then decreased with time (40 and 60 min). Even though ACAC failed to reduce food intake, injected ACAC disappeared faster from the circulation than injected D3HB. The data are consistent with the idea that oxidation of injected D3HB to ACAC reduces food intake in rats.

3-Hydroxybutyric Acid↗

PubMed1992

Antithrombin III, C1 inhibitor, methylglyoxal, and polymorphonuclear leukocytes in the development of vascular complications in diabetes mellitus.

Under conditions closely approximating those in vivo (100 mM sodium carbonate pH 7.3 with 0.9% NaCl, 37 degrees C), antithrombin III (AT III) and the C1 inhibitor (C1-INH) are inactivated by methylglyoxal (MG) with pseudofirst-order kinetics and second-order rate constants of 25.2 and 7.8 M-1 min-1, respectively. A study of the functional status of neutrophils from patients with diabetes mellitus (DM) prompts an idea that under hyperglycemia in the diabetic organism the polymorphonuclear leukocytes (PML) endure 'arousal' that is identical or analogous to their activation. Indeed, nonstimulated PML from DM patients display (i) an almost sixfold higher luminol-dependent chemiluminescence and (ii) a double rate of oxygen uptake as compared with those from healthy donors, and (iii) are capable of MG formation in the presence of acetoacetate, which in vivo may be an additional source of this inactivator of AT III and C1-INH in diabetic patients. Conditions leading to ketosis or lactic acidosis are discussed, and a probable scenario is proposed for the organismic deterioration in DM.

Acetoacetates↗

PubMed1981

Ontogenesis of the functional activity of rat olfactory bulb: autoradiographic study with the 2-deoxyglucose method.

An ontogenetic study of the uptake of [14C]2-deoxyglucose (2-DG) within the olfactory bulb was performed on rats of 3 age groups, 1, 9 and 21 days. Animals were exposed either to ethyl acetoacetate (EAA) or to a nest odor. Already in newborns, a glomerular activity characterized by small spots of increased 2-DG uptake, appeared in response to either odor stimulation. An ontogenetic development of this glomerular activity was observed with age: whereas the labeled glomerular foci were scanty in newborns, their number constantly increased with age until weaning; moreover, an increased proportion of foci overlaying 2 or 3 single glomeruli was noted in parallel with the postnatal maturation of the olfactory system. For the 3 age groups, whatever the odor stimulus, the glomerular activity seemed located in 2 main regions of the olfactory bulb, the lateral aspect and the posterior part of the medial aspect of the bulb. In newborns, no clear difference could be brought out between the patterns of glomerular activation related to EAA and to nest odor, respectively. In 9-day-old rats, the spatial patterns of distribution associated with the 2 odors were overlapping, but nevertheless different. These data are correlated with the postnatal maturation of the olfactory system.

Acetoacetates↗

PubMed1987

Effects of early chronic phenobarbital treatment on the maturation of energy metabolism in the developing rat brain. II. Incorporation of beta-hydroxybutyrate into amino acids.

The influence of phenobarbital (PhB) on the utilization of beta-hydroxybutyrate by the cerebral cortex and the cerebellum was studied in rats during postnatal maturation. The animals were treated from day 2 to day 35 after birth either by a daily injection of 50 mg/kg PhB or by saline. The rats were studied at 5 postnatal stages: 7, 10, 14, 21 and 35 days. Plasma beta-hydroxybutyrate and acetoacetate levels reached their peak values between 10 and 14 days after birth. The concentration of both ketone bodies was significantly higher in PhB- than in saline-treated rats between 10 and 35 days after birth. The total incorporation of [3-14C]beta-hydroxybutyrate into amino acids reached a peak value at 14 days after birth and was down to very low values at 35 days. It was higher in PhB- than in saline-treated rats. The specific radioactivity values of glutamate, glutamine, aspartate and GABA were significantly higher in PhB- than in saline-treated especially at 10 days after birth. These results demonstrate that a PhB treatment induces an increase in brain ketone body utilization in neonate rats, which is likely to balance the decrease in brain glucose utilization induced by this pharmacological treatment.

3-Hydroxybutyric Acid↗

PubMed1987

The size of mitral cells is altered when rats are exposed to an odor from their day of birth.

Rats were exposed to a moderate concentration of ethyl acetoacetate, amyl acetate, cyclohexanone or heptanol, for 69 days from postnatal day 1, whilst other rats were exposed to deodorized air, or the normal range of rat colony odors (Controls). The size of approximately 3% of all mitral cells in the olfactory bulb were measured using a computer-assisted method. As in previous studies in which stimulation began at day 14 or later, some regions of the olfactory bulb had cells that were significantly smaller than those of controls, and rats exposed to deodorized air generally had the smallest cells. Unlike in earlier studies, however, some regions of the olfactory bulb had cells that were significantly larger than similar regions of controls. The distribution of these changes appears to be odor-specific and consists of coronal patterns that extend throughout the rostro-caudal extent of the bulb. The different patterns obtained for the 4 odors used in this study provide evidence for a topographic coding of odor quality at the level of the mitral cells.

Acetoacetates↗

PubMed1988

Effect of glycerol on gluconeogenesis in isolated rabbit kidney cortex tubules.

In renal tubules isolated from fed rabbits glycerol is not utilized as a glucose precursor, probably due to the rate-limiting transfer of reducing equivalents from cytosol to mitochondria. Pyruvate and glutamate stimulated an incorporation of [14C]glycerol to glucose by 50- and 10-fold, respectively, indicating that glycerol is utilized as a gluconeogenic substrate under these conditions. Glycerol at concentration of 1.5 mM resulted in an acceleration of both glucose formation and incorporation of [14C]pyruvate and [14C]glutamate into glucose by 2- and 9-fold, respectively, while it decreased the rates of these processes from lactate as a substrate. In the presence of fructose, glycerol decreased the ATP level, limiting the rate of fructose phosphorylation and glucose synthesis. As concluded from the 'cross-over' plots, the ratios of both 3-hydroxybutyrate/acetoacetate and glycerol 3-phosphate/dihydroxyacetone phosphate, as well as from experiments performed with methylene blue and acetoacetate, the stimulatory effect of glycerol on glucose formation from pyruvate and glutamate may result from an acceleration of fluxes through the first steps of gluconeogenesis as well as glyceraldehyde-3-phosphate dehydrogenase. As inhibition by glycerol of gluconeogenesis from lactate is probably due to a marked elevation of the cytosolic NADH/NAD+ ratio resulting in a decline of flux through lactate dehydrogenase.

Acetoacetates↗