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PubMed1983

Effect of dietary excess leucine on the levels of branched chain alpha-keto acids and ketone bodies in blood and the liver of rats.

Male rats were fed either a 10% casein diet or a 10% casein diet supplemented with 5% leucine, and the levels of alpha-ketoisocaproic acid and ketone bodies were analyzed in blood and the liver. alpha-Ketoisocaproic acid in plasma increased significantly on the 1st day of feeding the leucine-supplemented diet and was maintained on the high level during the experimental period of 7 days. Other branched chain alpha-keto acids tended to decrease in plasma. beta-Hydroxybutyric acid in blood doubled its amount on the 1st day on the high leucine diet and was maintained high during the experimental period. The sum of acetoacetic acid and beta-hydroxybutyric acid in blood was kept on a level twice as high as that of the control group. Ketone bodies in the liver were similarly increased and the sum of acetoacetic acid and beta-hydroxybutyric acid in the liver corresponded to the level found inhibitory to NAD biosynthesis in in vitro system [YAMADA, O., et al.: Int. J. Vit. Nutr. Res. 53, 184 (1983)].

Animals↗

PubMed1982

Changes in certain metabolic parameters in horses associated with food deprivation and endurance exercise.

Total and individual non-esterified fatty acids (NEFA), pyruvate, lactate, alpha ketoglutarate, acetoacetate, beta hydroxybutyrate, glucose and insulin were measured in horses during an 80 km endurance ride and during four days of food deprivation. In the latter group venous blood-gas and acid-base parameters, and plasma cortisol concentrations were also measured. During exercise and food deprivation the NEFA became considerably elevated, the predominant of which were oleic (35 per cent), palmitic (24 per cent), linoleic (19 per cent) and linolenic (10 per cent). By one hour after feeding total NEFA fell to approximately 20 per cent of 12 hour fasting concentrations. This was associated with a four fold rise in insulin. Small though significant increases occurred in lactate, acetoacetate and beta hydroxybutyrate after the 80 km endurance ride. It was concluded that a ketone pathway is relatively unimportant in the horse, probably due to the ability of the liver to maintain glycogenolysis.

Animals↗

PubMed1982

4-Bromocrotonic acid, an effective inhibitor of fatty acid oxidation and ketone body degradation in rat heart mitochondria. On the rate-determining step of beta-oxidation and ketone body degradation in heart.

4-Bromocrotonic acid was found to effectively inhibit respiration supported by either palmitoylcarnitine or acetoacetate in coupled rat heart mitochondria. Partial inhibition was observed when 3-hydroxybutyrate served as a substrate, whereas pyruvate-supported respiration was unaffected by the inhibitor. Thus, 4-bromocrotonic acid inhibits fatty acid oxidation and ketone body degradation. When the enzymes of beta-oxidation and ketone body degradation were assayed in mitochondria preincubated with 4-bromocrotonic acid, only 3-ketoacyl-CoA thiolase and acetoacetyl-CoA thiolase were found to be inactive. Evidence is presented for the enzymatic conversion of 4-bromocrotonic acid to 3-keto-4-bromobutyryl-CoA which effectively inhibits both thiolases. A kinetic evaluation of the inhibitions caused by 4-bromocrotonic acid in coupled rat heart mitochondria demonstrated that 3-ketoacyl-CoA thiolase and respiration supported by palmitoyl carnitine are inactivated at equal rates. However, acetoacetyl-CoA thiolase was inactivated more rapidly than was respiration supported by acetoacetate. It is suggested that the thiolase-catalyzed step is rate-limiting in beta-oxidation or is as slow as other reactions are. In contrast the thiolytic cleavage of acetoacetyl-CoA does not seem to be rate-limiting in ketone body degradation.

3-Hydroxyacyl CoA Dehydrogenases↗

PubMed1982

Uncoupling of Na+-dependent solute transport in renal brush border membranes of maleate-treated rats.

The effect of maleate on the Na+-dependent transport of glucose, phenylalanine and phosphate in the renal brush border membranes (BBM) was studied. It was found that maleate as such had no effect on the isolated BBM vesicles. In BBM isolated from kidney cortex slices which were incubated with maleate, as well as in BBM isolated from the kidneys of maleate-treated rats, an inhibition of the Na+-dependent glucose and phenylalanine transport was observed, whereas the Na+-dependent phosphate transport was stimulated. In kidney slices these effects were prevented by the simultaneous addition of acetoacetate to the incubation medium. The permeability to Na+ ions was increased in the brush border membranes isolated from maleate-treated renal tissue. Cyclic AMP level was decreased nearly by half in the kidneys of maleate-treated rats. It is concluded that the formation of maleyl-CoA, which is prevented by acetoacetate, is a prerequisite for the effects of maleate on the BBM. The data suggest that the inhibition of Na+-dependent glucose and phenylalanine transport results from the uncoupling of Na+ and solute transport, due to increased permeability of the BBM to Na+. The stimulation of the phosphate transport system results probably from a decrease of cell cyclic AMP level. It is suggested that the uncoupling of Na+ and solute transport in the BBM is responsible for the generalized impairment by maleate of solute reabsorption in the renal proximal tubules.

Amino Acids↗

PubMed1977

Effect of starvation on muscle glucose metabolism: studies with the isolated perfused rat hindquarter.

Studies in man and experimental animals suggest that the metabolism of glucose by skeletal muscle is depressed during starvation. To investigate the basis for this, the effect of starvation on the uptake and disposition of glucose in skeletal muscle was studied in the isolated perfused rat hindquarter. In contrast to earlier work carried out in heart, neither glucose uptake, whether stimulated by insulin or exercise, nor glycolysis were depressed by 48 hr of starvation or by perfusion of the hindquarter with acetoacetate, palmitate, or octanoate. Glucose oxidation, assessed from the oxidation of 1-[14C]lactate, was depressed by approximately 75% in starved rats and by 30% in fed rats perfused with acetoacetate. Exercise increased lactate oxidation 10-fold in both fed and starved rats; however, the relative difference between the groups persisted. In general, changes in lactate oxidation were paralleled by changes in the activity of pyruvate dehycrogenase (active form). The data suggest that glucose metabolism in skeletal muscle is inhibited during starvation at the step of pyruvate oxidation and that this inhibition persists during exercise. The also suggest that the diminution of glucose uptake that occurs in skeletal muscle of intact organisms during starvation may not be related to the presence of high concentrations of free fatty acids and ketone bodies.

Acetyl Coenzyme A↗

PubMed1995

[Arterial plasma keton body levels during isoflurane anesthesia and surgery].

The authors measured arterial plasma levels of acetoacetate, 3-hydroxybutyrate, free fatty acid and the blood levels of lactate and glucose to evaluate fat metabolism during isoflurane anesthesia and surgery in twenty patients who ranged in age from 17 to 67 years. They underwent non-abdominal surgery (orthopedic surgery) or abdominal surgery (gastrointestinal or gynecological surgery). The operation started at 9 AM following starvation after 9 PM of the day before surgery. Anesthesia was induced with intravenous thiopental followed by intravenous succinylcholine to facilitate tracheal intubation, and maintained with isoflurane in 50 % nitrous oxide and 50 % oxygen. Vecuronium was given intravenously during surgery. Lactated Ringer's solution at a speed of 5-15 ml.kg-1.h-1 was also administered intravenously throughout the procedures. Patients who had received glucose solution or blood transfusion were excluded. Plasma acetoacetate and 3-hydroxybutyrate levels increased significantly with surgical stimulation in both groups and they were slightly higher in the abdominal group than those in the non-abdominal group. However there was no statistical difference in plasma keton body levels between the groups. Mild increases in plasma free fatty acid and blood lactate levels were detected during surgery in both groups to the same extent. Blood glucose increased significantly during surgery in both groups and the increase was statistically higher in the abdominal group than that in the non-abdominal group. The findings suggest that there is no difference in fat metabolism between non-abdominal and abdominal groups during surgical intervention lasting as long as 3 hours when patients are starved and do not receive any glucose during surgery.

Adolescent↗

PubMedDate not supplied

Arterial ketone body ratio and adenosine triphosphate concentration in hepatic ischemia and reperfusion.

BACKGROUND/AIMS: The arterial ketone body ratio (AKBR) and the cellular adenosine triphosphate (ATP) concentration have been proposed as indicators of liver function. However, recent studies of the utility of the AKBR as a biochemical marker have been called into question. Furthermore, there is no practical data defining the relationship between ATP concentration and ischemia-reperfusion (IR) changes during liver surgery. METHODOLOGY: The relationship of the AKBR and arterial ATP concentration to IR during hepatectomy was investigated. In 20 patients who underwent hepatectomy, arterial acetoacetate, beta-hydroxybutyrate, and ATP concentrations were measured. The ratio of acetoacetate to beta-hydroxybutyrate (AKBR) was calculated before and after vascular occlusion. RESULTS: The AKBR 15 minutes after clamping was lower than the preclamping values in all of the patients. It increased after unclamping, returning toward the preclamping levels. An AKBR of less than 0.5 prior to clamping did not correlate with preoperative hepatocellular function. An AKBR of less than 0.7 throughout IR was not a consistent risk factor for postoperative complications and liver dysfunction. The arterial ATP concentration did not correlate with the changes during IR or with preoperative hepatocellular function. CONCLUSIONS: Although the AKBR changed during IR as a general indicator of cellular activity, the absolute value of the AKBR was not an accurate predictor of liver function. The arterial ATP concentration also was not a suitable clinical biochemical marker of hepatic function.

Adenosine Triphosphate↗

PubMed1965

INFLUENCE OF ETHANOL ON THE LIVER METABOLISM OF FED AND STARVED RATS.

1. The influence of ethanol on the metabolism of livers from fed and starved rats has been studied in liver-perfusion experiments. Results have been obtained on oxygen consumption and carbon dioxide production, on glucose release and uptake by the liver and on changes in the concentrations of lactate and pyruvate and of beta-hydroxybutyrate and acetoacetate in the perfusion medium. 2. Oxygen consumption and carbon dioxide production were lower in livers from starved rats than in livers from fed rats. Ethanol had no effect on the oxygen consumption of either type of liver. After the addition of ethanol to the perfusion medium carbon dioxide production ceased almost completely, the change being faster in livers from starved rats. 3. With livers from fed rats glucose was released from the liver into the perfusion medium. This release was slightly greater when ethanol was present. With livers from starved rats no release of glucose was observed, and when ethanol was added a marked uptake of glucose from the medium was found. A simultaneous release of glycolytic end products, lactate and pyruvate, into the medium occurred. 4. Acetate was the main metabolite accumulating in the perfusion medium when ethanol was oxidized. With livers from starved rats a slightly increased formation of ketone bodies was found when ethanol was present. 5. The lactate/pyruvate concentration ratio in the perfusion medium increased from 10 to 87 with livers from fed rats and from 20 to 171 with livers from starved rats when the livers were perfused with ethanol in the medium. The beta-hydroxybutyrate/acetoacetate concentration ratio increased from 0.8 to 7.6 with livers from fed rats and from 1.0 to 9.5 with livers from starved rats when ethanol was added to the medium. 6. The effects of ethanol are discussed and related to changes in the redox state of the liver that produce new conditions for some metabolic pathways.

Acetoacetates↗

PubMed1965

ACCELERATION OF RENAL GLUCONEOGENESIS BY KETONE BODIES AND FATTY ACIDS.

1. Acetoacetate or short-chain fatty acids (acetate, butyrate, propionate, n-hexanoate, n-octanoate) accelerate the rate of glucose formation from lactate, fumarate and other precursors in slices of kidney cortex (rat, rabbit, sheep). The cause of this acceleration has been investigated. 2. There are two different mechanisms of acceleration. At low concentrations of glucogenic precursors the acceleration is mainly due to a ;sparing' action. The substances which accelerate are oxidizable and serve as fuel of respiration in place of the glucogenic precursor. This is indicated by the fact that the ratio lactate used/glucose formed falls in the presence of the accelerators and approaches the value 2. 3. At high concentrations of lactate the acceleration appears to be mainly due to the activation of pyruvate carboxylase by acetyl-coenzyme A. The evidence in support of this is summarized. The results indicate that the activation of pyruvate carboxylase by acyl-coenzyme A discovered by Utter & Keech (1963) in purified enzyme preparations also occurs in crude tissue homogenates and can play a part in the control of oxaloacetate synthesis and gluconeogenesis.

Acetates↗

PubMed1981

Changes in blood ketone body ratio: their significance after major hepatic resection.

Changes in the ratio of acetoacetate to 3-hydroxybutyrate (the ketone body ratio) in arterial blood were investigated after massive liver resection in patients and rabbits. In a patient who had had a successful hepatectomy, the blood ketone body ratio decreased rapidly after the operation and then returned to the preoperative level; whereas in a patient who had had an unsuccessful hepatectomy, the blood ketone body ratio did not decrease rapidly after the operation. In 70% hepatectomized rabbits, the blood ketone body ratio decreased maximally nine hours after hepatectomy and then returned gradually to a normal level. The blood ketone body ratio paralleled the hepatic energy charge after 70% hepatectomy in rabbits. The measurement of the blood ketone body ratio is very useful for evaluation of the energy status of the remnant liver.

Acetoacetates↗

PubMed1983

Metabolic abnormalities associated with postoperative organ failure. A redox theory.

We studied metabolic abnormalities of postoperative organ failure in 55 patients and classified them into four groups according to the postoperative changes in the arterial blood-ketone body ratio (acetoacetic acid-beta-hydroxybutyric acid) reflecting hepatic mitochondrial redox potential: patients in group A had no decrease below 0.7, patients in group B had a transient decrease to 0.4, patients in group C had a progressive decrease to below 0.4, and patients in group D (terminal stage) had a decrease to below 0.25. All group A and B patients tolerated their operations well; the group C and D patients had multiple organ failure. In groups B, C, and D, plasma concentrations of alanine, proline, phenylalanine, and tyrosine were negatively correlated with the blood--ketone body ratio and the molar ratios between the plasma concentrations of branched-chain amino acids and aromatic amino acids were positively correlated with the blood--ketone body ratio. Hepatic energy deficit associated with decreasing blood-ketone body ratio may be the metabolic basis of postoperative organ failure.

3-Hydroxybutyric Acid↗

PubMed1999

Role of reactive oxygen species (ROS) in the diabetes-induced anomalies in rat embryos in vitro: reduction in antioxidant enzymes and low-molecular-weight antioxidants (LMWA) may be the causative factor for increased anomalies.

A disturbed embryonic antioxidant defense mechanism may play a major role in diabetes-induced teratogenesis. We therefore studied the antioxidant capacity of 10.5-day-old rat embryos and their yolk sacs after culture for 28 hr in vitro under diabetic conditions (3 mg/ml glucose, 2 mg/ml beta-hydroxybutyrate (BHOB) and 10 microg/ml of acetoacetate), as compared with control embryos in vitro. We found a high rate of congenital anomalies, decreased growth and protein content, and a decrease in the activity of both superoxide dismutase (SOD) and catalase (CAT) under diabetic conditions, as compared with controls. The reducing power, which reflects the concentration and type of water-soluble and of lipid-soluble low-molecular-weight antioxidants (LMWA), was measured by cyclic voltammetry. Generally, LMWA were reduced in the embryos and yolk sacs under diabetic conditions. In the water-soluble fraction of control embryos and yolk sacs, two peak potentials were found, indicating two major groups of LMWA, while only one peak potential was found under diabetic conditions, indicating that an entire group of LMWA is missing. HPLC studies have demonstrated a decrease in vitamin C (water-soluble fraction) and in vitamin E (lipid-soluble fraction) under diabetic culture conditions, and an increase in uric acid. Generally, the concentration of LMWA was higher in the embryos than in the yolk sac. LMWA concentration, protein content, and antioxidant enzyme activity were lower in the malformed experimental embryos than in experimental embryos without anomalies. The addition of vitamins C and E to the diabetic culture medium abolished the deleterious effects of the diabetic serum on the embryos. The disturbed antioxidant defense mechanism under diabetic conditions may be explained, at least in part, by a direct effect of diabetic metabolic factors on the activity of antioxidant enzymes and on the concentration of reducing equivalents. This, in turn, may be embryotoxic.

3-Hydroxybutyric Acid↗

PubMed1996

Prenatal diagnosis of succinyl-coenzyme A:3-ketoacid coenzyme A transferase deficiency.

Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency is a rare disorder of ketone body catabolism. In the present study, we prenatally diagnosed SCOT deficiency in a fetus in a family of which the proband was the first patient with SCOT deficiency identified in Japan, by analysis of enzyme activity levels in samples of chorionic villi and cultured amniocytes. In the fetus of the family, SCOT activity was not detected in either chorionic villi or cultured amniocytes. Since the levels of SCOT activity in control chorionic villi were close to our minimal detectable level and were much lower than those in control cultured amniocytes, enzyme assay in cultured amniocytes was more feasible than that in chorionic villi for prenatal diagnosis of SCOT deficiency. No elevated accumulation of 3-hydroxybutyrate or acetoacetate was detected in the amniotic fluid of the fetus. To our knowledge, this report is the first of prenatal diagnosis of SCOT deficiency.

3-Hydroxybutyric Acid↗

PubMed2006

Unexplained acidosis of malnutrition: a study by ion-exchange chromatography/mass spectrometry.

Keto-acidosis is usually associated with uncontrolled diabetes and typically poses few diagnostic problems when presenting as hyperglycaemia, metabolic acidosis and a high anion gap. An emaciated patient suffering from Duchenne Muscular Dystrophy and volume depletion presented with acidosis of unknown origin. Preliminary investigations appeared to rule out lactic acidosis, diabetic keto-acidosis and acidosis due to base loss. We have previously reported a technique utilizing liquid chromatography coupled to mass spectrometry (LC-MS) which can be used to characterize the underlying aetiology of acidosis and applied it to ultrafiltrate derived from a blood sample taken from this patient. The anion profile obtained on the chromatogram showed elevated levels of acetoacetate and hydroxybutyrate but no evidence of lactic acidosis, nor was the profile typical of that seen in 'unexplained' acidosis. We concluded that the patient was suffering from keto-acidosis associated with starvation and dehydration, the biochemical features being obscured by both the patient's chronic malnutrition and minimal muscle mass. A combination of enteral feeding and rehydration led to prompt resolution of the patient's metabolic acidosis.

Acetoacetates↗

PubMed1982

Identification of 4,6-dioxoheptanoic acid (succinylacetone), 3,5-dioxooctanedioic acid (succinylacetoacetate) and 4-Oxo-6-hydroxyheptanoic acid in the urine from patients with hereditary tyrosinemia.

In the urine from patients with hereditary tyrosinemia, three characteristic compounds have been found. They have been identified as 4,6-dioxoheptanoic acid (succinylacetone), 3,5-dioxooctanedioic acid (succinyl-acetoacetate) and 4-oxo-6-hydroxyheptanoic acid. The identities have been established by mass spectrometry of several derivatives, and by comparison with a synthetic sample of 4,6-dioxoheptanoic acid.

Acetoacetates↗

PubMed2004

Fungal aerobic reductive dechlorination of ethyl 2-chloroacetoacetate by Saccharomyces cerevisiae: mechanism of a novel type of microbial dehalogenation.

Saccharomyces cerevisiae reduces the beta-keto ester ethyl 2-chloroacetoacetate to the respective chiral cis- and trans-beta-hydroxy esters. In the course of chiral reduction, competing dehalogenation of the xenobiotic substrate to ethyl acetoacetate occurs, in a reaction mediated by cytosolic glutathione (GSH). Mechanistically, the dechlorination is a novel type of glutathione-dependent dehalogenation catalysed by an as yet unidentified glutathione-dependent dehalogenase. The first step consists of a nucleophilic replacement of the chloride substituent by glutathione. In the subsequent enzyme-catalysed step, a second glutathione molecule liberates the dehalogenation product by thiolytic attack at the thioether bridge, resulting in a net transfer of two electrons to the substrate and in the formation of glutathione disulfide (GSSG). Being effective under aerobic conditions and catalysed by a fungus, this reductive dechlorination of an aliphatic substrate is an outstanding example of a novel, glutathione-mediated microbial dehalogenation.

Acetoacetates↗

PubMed1977

[Behavior of certain parameters of lipid and energy metabolism. IV. Regulation of lipid and energy metabolism in livers and race and mini pigs].

To characterize the lipid and the energy metabolism in the livers of genetically different types of pigs (land race pig and mini pig), the authors determined the activities of enzymes typical of and limiting these metabolic pathways. Furthermore, they measured the concentrations of typical metabolites and ascertained parameters that are of importance in energy metabolism. The concentrations of acetyl CoA and free fatty acids in the livers of mini pigs were significantly greater than those in the livers of land race pigs, whereas the cholesterol, glycerol, triglyceride and acetoacetate concentrations were reduced. The activities of glucose-6-phosphate dehydrogenase (E.C.1.1.1.49.), citrate synthase (E.C.4.1.3.7.) and ATP citrate lyase (E.C.4.1.3.8.) were lower in the livers of mini pigs than in the livers of land race pigs, whereas the activity of fatty acid synthase was higher. The concentrations of cyclic 3',5'-adenosine monophosphate (AMP) and adenosine diphosphate (ADP) were lower in the livers of mini pigs than in those of land race pigs. In land race pigs, the metabolic process seems, therefore, to be determined in favour of the degradation of free fatty acids and of the generation of energy. In mini pigs, lipogenesis in the liver appears to be the decisive metabolic pathway. The possibility of a higher coordinating control mechanism of the lipid and the energy metabolism is discussed.

ATP Citrate (pro-S)-Lyase↗

PubMed1986

1H NMR studies of urine during fasting: excretion of ketone bodies and acetylcarnitine.

High-resolution 1H NMR spectroscopy has been applied to a study of urine from five normal human subjects during a 48-h period of fasting and for 22 h thereafter. The excretion rates of all three ketone bodies (acetoacetate, 3-D-hydroxybutyrate, and acetone), acetylcarnitine, creatinine, and sarcosine during this period were measured. Parallel increases in the excretion of the ketone bodies and acetylcarnitine were observed during fasting with little change in the output of creatinine and sarcosine.

3-Hydroxybutyric Acid↗