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PubMed1996

Substrate selection early after reperfusion of ischemic regions in the working rabbit heart.

Several substrates are available in vivo for oxidation by the myocardium. Although substrate selection has been studied extensively in normoxic myocardium, relatively little is known about substrate preference very early during reperfusion after ischemia. Carbon-13 isotopomer analysis was used to study substrate usage by nonischemic and reperfused-ischemic myocardium in a working heart that was subjected to 15 min or regional ischemia and reperfused for 5 min. Compared with nonischemic myocardium, the contribution of acetoacetate to acetyl coenzyme A was increased in the reperfused-ischemic region, and the contribution of exogenous lactate was decreased. Free fatty acid oxidation, however, was not different in the two regions. These results indicate that (1) early during reperfusion, ketone body oxidation may be more significant than has been emphasized, (2) the relative contribution of fatty acids to acetyl coenzyme A is not sensitive to ischemia followed by reperfusion, and (3) Carbon-13 magnetic resonance spectroscopy methods may be used for analysis of spatial heterogeneity of metabolism in the heart.

Acetoacetates↗

PubMed1994

Effects of dogfish urotensin II on lipid mobilization in the fasted dogfish, Scyliorhinus canicula.

Previous studies, both in vitro and in vivo, have shown that urotensin II stimulates hepatic release of nonesterified fatty acids in teleost fish, but the effects of the peptide on lipid mobilization in elasmobranchs are unknown. Infusions of synthetic dogfish urotensin II (40 pmol/min/kg for 30 min followed by 400 pmol/min/kg for 30 min) into the first afferent gill artery of the fasted, unrestrained dogfish, Scyliorhinus canicula (n = 6), produced no significant change in the circulating concentrations of acetoacetate, 3-hydroxybutyrate, and triacylglycerols. Circulating nonesterified fatty acids were undetectable (< 0.1 mmol/liter) both before and after the urotensin II infusions. There was no significant change in the circulating concentrations of glucose and lactate during either the low- or the high-dose infusions. The data support the hypothesis that lipid is converted primarily to ketone bodies in the livers of elasmobranch fish and do not indicate a role for urotensin II in regulating either lipid or glycogen mobilization.

3-Hydroxybutyric Acid↗

PubMed2002

Purification, characterization, and biological activity of insulins from the spotted dogfish, Scyliorhinus canicula, and the hammerhead shark, Sphyrna lewini.

Insulin was purified from pancreatic extracts of two elasmobranch species belonging to different families in the order Carcharhiniformes, the European spotted dogfish, Scyliorhinus canicula (Scyliorhinidae), and the hammerhead shark, Sphyrna lewini (Carcharhinidae). The amino acid sequence of dogfish insulin was established as A-chain GIVDHCCRNT(10)CSLYDLEGYC(20)NQ and B-chain LPSQHLCGSH(10)LVETLYFVCG(20)QKGFYYVPKV(30). The primary structure of hammerhead shark insulin was similar to that of dogfish insulin with only 2 amino acid substitutions at A8 (R --> H) and B30 (V --> I). The elasmobranch insulins were markedly different from human insulin (17 amino acid substitutions) but all the residues in human insulin that are believed to be important in determining the receptor binding conformation (B6, B8, B11, B13, B23, B24, B25, A2, A3, and A19) have been conserved in the elasmobranch insulins with the exception of the conservative substitution Phe --> Tyr at B25. Consistent with this, dogfish and human insulin showed almost identical binding affinity to the recombinant solubilized human insulin receptor (K(D) values of 14.0 and 18.6 pM, respectively; relative potency 133%). Previous studies have shown that bovine insulin produces severe and sustained hypoglycemia in elasmobranchs but the effect is of slow onset. Bolus arterial injections of dogfish insulin (10 nmol x kg(-1)) into unanesthetized, fasting dogfish (n = 9) produced no changes in blood glucose, 3-hydroxybutyrate, and acetoacetate concentrations over a 4-h period. In a second series of experiments (n = 7), dogfish insulin (10 nmol x kg(-1)) produced a significant (P < 0.05) fall in blood glucose after 12 h that persisted for at least 48 h, but no change in ketone body concentrations. The data indicate that the metabolic actions of an endogenous elasmobranch insulin in an elasmobranch are similar to those previously described for mammalian insulin.

3-Hydroxybutyric Acid↗

PubMed2000

Recognition of structurally diverse substrates by type II 3-hydroxyacyl-CoA dehydrogenase (HADH II)/amyloid-beta binding alcohol dehydrogenase (ABAD).

Human type II hydroxyacyl-CoA dehydrogenase/amyloid-beta binding alcohol dehydrogenase (HADH II/ABAD) is an oxidoreductase whose salient features include broad substrate specificity, encompassing 3-hydroxyacyl-CoA derivatives, hydroxysteroids, alcohols and beta-hydroxybutyrate, and the capacity to bind amyloid-beta peptide, leading to propagation of amyloid-induced cell stress. In this study, we examine the structure and enzymatic activity of the homologous rat HADH II/ABAD enzyme. We report the crystal structure of rat HADH II/ABAD as a binary complex with its NADH cofactor to 2.0 A resolution, as a ternary complex with NAD(+) and 3-ketobutyrate (acetoacetate) to 1.4 A resolution, and as a ternary complex with NADH and 17 beta-estradiol to 1.7 A resolution. This first crystal structure of an HADH II confirms these enzymes are closely related to the short-chain hydroxysteroid dehydrogenases and differ substantially from the classic, type I 3-hydroxyacyl-CoA dehydrogenases. Binding of the ketobutyrate substrate is accompanied by closure of the active site specificity loop, whereas the steroid substrate does not appear to require closure for binding. Despite the different chemical nature of the two bound substrates, the presentation of chemical groups within the active site of each complex is remarkably similar, allowing a general mechanism for catalytic activity to be proposed. There is a characteristic extension to the active site that is likely to accommodate the CoA moiety of 3-hydroxyacyl-CoA substrates. Rat HADH II/ABAD also binds amyloid-beta (1-40) peptide with a K(D) of 21 nM, which is similar to the interaction exhibited between this peptide and human HADH II/ABAD. These studies provide the first structural insights into HADH II/ABAD interaction with its substrates, and indicate the relevance of the rodent enzyme and associated rodent models for analysis of HADH II/ABAD's physiologic and pathophysiologic properties.

3-Hydroxyacyl CoA Dehydrogenases↗

PubMed1985

Glucose, lactate, and ketone body utilization by human mammary carcinomas in vivo.

The glucose uptake rate of human mammary carcinomas transplanted into nude rats is comparable to values obtained in isotransplanted rodent tumors. The glucose uptake decreases with increasing tumor wet weight and is linearly related to the glucose availability. Most tumors release lactate, the rate being linearly related to the glucose uptake rate. Tumors use acetoacetate and beta- hydroxybutyrate as substrates. Additionally, human mammary carcinomas may have the ability for ketogenesis probably depending on the metabolic state. Using the epigastric pouching technique, human mammary carcinoma xenografts in nude rats seem to be a valid model for systematic investigations of the energy supply of human tumors.

3-Hydroxybutyric Acid↗

PubMed1996

Leishmania donovani: metabolite mapping of promastigotes using proton nuclear magnetic resonance spectroscopy.

Proton nuclear magnetic resonance spectroscopy was used for studying the intracellular metabolite profile of promastigotes of Leishmania donovani. The major intracellular metabolites observed in the promastigotes were acetate, alanine, succinate, glycine, alpha-glycerophosphorylcholine, acetoacetate, arginine and ethanol. A comparative study of the intracellular metabolite profile of promastigotes of different strains of L. donovani showed that, all the major intracellular metabolites were present in promastigotes of different strains. A quantitative estimation of metabolites showed a strain specific (Finger print) metabolite profile which can be used for strain/species identification/differentiation.

Acetates↗

PubMed1990

Anaerobic degradation of acetone by Desulfococcus biacutus spec. nov.

From anaerobic digestor sludge of a waste water treatment plant, a gram-negative, strictly anaerobic sulfate-reducing bacterium was isolated with acetone as sole organic substrate. The bacterium was characterized as a new species, Desulfococcus biacutus. The strain grew with acetone with doubling times of 72 h to 120 h; the growth yield was 12.0 (+/- 2.1) g x [mol acetone]-1. Acetone was oxidized completely, and no isopropanol was formed. In labelling studies with 14CO2, cell lipids (including approx. 50% PHB) of acetone-grown cells became labelled 7 times as high as those of 3-hydroxy-butyrate-grown cells. Enzyme studies indicated that acetone was degraded via acetoacetyl-CoA, and that acetone was channeled into the intermediary metabolism after condensation with carbon dioxide to a C4-compound, possibly free acetoacetate. Acetoacetyl-CoA is cleaved by a thiolase reaction to acetyl-CoA which is completely oxidized through the carbon monoxide dehydrogenase pathway. Strain KMRActS was deposited with the Deutsche Sammlung von Mikroorganismen, Braunschweig, under the number DSM 5651.

3-Hydroxybutyric Acid↗

PubMed1977

[The ketone bodies in the hemolymph of Biomphalaria glabrata under starvation and infection with Schistosoma mansoni (author's transl)].

The metabolism of the snail Biomphalaria glabrata stressed by five days' starvation as well as by infection with Schistosoma mansoni was examined with regard to the metabolism of ketone bodies. Previous studies in the metabolism of this host--parasite relationship always resulted in changes in the same direction with starvation as well as with infection. Contrary to that the concentration of acetoacetate and beta-hydroxybutyrate measured in the hemolymph decreased significantly with starvation but increased significantly with infection. The following problems concerning the ketone body metabolism are discussed: on the one hand the differences between infected and starved snails, and on the other hand the differences between the snails and the mammals as well as in the invertebrates so far investigated.

Acetoacetates↗

PubMed1992

The effects of different plasma insulin concentrations on lipolytic and ketogenic responses to epinephrine in normal and type 1 (insulin-dependent) diabetic humans.

This study was performed to verify: (1) the ability of different insulin concentrations to restrict the lipolytic and ketogenic responses to exogenous epinephrine administration; (2) whether the ability of insulin to suppress the lipolytic and ketogenic responses during epinephrine administration is impaired in Type 1 (insulin-dependent) diabetic patients. Each subject was infused on separate occasions with insulin at rates of 0.2, 0.4, and 0.8 mU.kg-1.min-1 while normoglycaemic. To avoid indirect adrenergic effects on endocrine pancreas secretions, the so-called "islet clamp" technique was used. Rates of appearance of palmitic acid, acetoacetate, and 3-hydroxybutyrate were simultaneously measured with an infusion of 13C-labelled homologous tracers. After a baseline observation period epinephrine was exogenously administered at a rate of 16 ng.kg-1.min-1. At low insulin levels (20 microU/ml) the lipolytic response of comparable magnitude was detected in normal and Type 1 diabetic patients. However, the ketogenic response was significantly higher in Type 1 diabetic patients. During epinephrine administration, similar plasma glucose increments were observed in the two groups (from 4.74 +/- 0.53 to 7.16 +/- 0.77 mmol/l (p less than 0.05) in Type 1 diabetic patients and from 4.94 +/- 0.20 to 7.11 +/- 0.38 mmol/l (p less than 0.05) in normal subjects, respectively). At intermediate insulin levels (35 microU/ml) no significant differences were found between Type 1 diabetic patients and normal subjects, whereas plasma glucose levels rose from 4.98 +/- 0.30 to 6.27 +/- 0.66 mmol/l (p less than 0.05) in Type 1 diabetic patients, and from 5.05 +/- 0.13 to 6.61 +/- 0.22 mmol/l (p less than 0.05) in normal subjects. At high insulin levels (70 microU/ml) the lipolytic response was detectable only in Type 1 diabetic patients; the ketogenic response was reduced in both groups. During the third clamp, a significant rise in plasma glucose concentration during epinephrine infusion was observed in both groups. In conclusion this study shows that at low insulin levels Type 1 diabetic patients show an increased ketogenic response to epinephrine, despite their normal nonesterified fatty acid response. Instead, high insulin levels are able to restrict the ketogenic response to epinephrine in both normal and Type 1 diabetic subjects, although there is a still detectable lipolytic response in the latter. In the presence of plasma free insulin levels that completely restrict the ketogenic response in the same group, there is still a distinct glycaemic response. Plasma insulin levels in Type 1 diabetic patients are a major determinant of the metabolic response to epinephrine.

Acetoacetates↗

PubMed1982

Fat-derived fuels during a 24-hour fast in children.

We examined the availability of fat-derived fuels in 23 normal children aged 1.9 to 16.7 years who fasted for 24 h. We found a rapid and progressive rise in the blood concentrations of free fatty acids (FFA) and ketones. There was a highly significant negative correlation between the concentrations of beta-hydroxybutyrate (beta OHB) and glucose and also between beta OHB and age. With time, the ratio of beta OHB to acetoacetate (AcAc) progressively increased. We briefly review the vital role of ketones in the adaptation to fasting and point out that qualitative tests of ketones can be misleading. Our results indicate that quantitative determinations are essential in the evaluation of suspected disorders of fuel metabolism and that the results must be interpreted according to the age of the child, the duration of fasting, and the concomitant concentrations of glucose.

Acetoacetates↗

PubMed1986

Ambient temperature and ketone body plasma concentration in fasting geese.

The effect on ketonemia of alternate exposure to ambient temperatures (Ta) of 25 and 5 degrees C was investigated in fasting geese. Three experimental birds were compared to three controls continuously exposed to 25 degrees C Ta while fasting. During the first 9 days of fasting, when both groups were exposed to 25 degrees C, plasma concentration of beta-hydroxybutyrate (beta-OHB) increased similarly in both, from 0.10 +/- 0.02 to 6.62 +/- 0.71 mmol X L-1. It later plateaued at 8-9 mmol X L-1 in the control birds. When the experimental birds were exposed to 5 degrees C Ta between the 9th and 15th day of the fast, it increased further during the first 24 h but thereafter decreased of 57%, from 8.62 +/- 1.56 to 3.73 +/- 1.24 mmol X L-1. This decrease was reversed within the 6 days of return to 25 degrees C Ta. In both groups, plasma acetoacetate (AcAc) concentration remained very low during the fast: 51 +/- 1 mumol X L-1. This reversible cold-induced effect on ketonemia may be used for investigating the possible role of ketone bodies in protein sparing during fasting.

3-Hydroxybutyric Acid↗

PubMed1977

Effects of aldosterone on lipid metabolism and renal oxygen consumption in the rat.

The plasma level of free fatty acids (FFA) in adrenalectomized rats increases by 50% after treatment with aldosterone (2 microng/100 g rat). Lipolytic activity in peripheral fat tissue is lowered after adrenalectomy and doubles after in vivo administration of aldosterone to adrenalectomized rats (measured as free fatty acid release in vitro from epididymal fat tissue). Lypolysis of adipose tissue stimulated by the in vitro presence of ACTH also increases after in vivo administration of aldosterone. Incorporation of intravenously administered label from U-14C-palmitate into total extractable lipid of renal tissue is augmented 3 h after aldosterone administration to adrenalectomized rats, while no increase of the radioactivity is observed in total lipid from liver tissue. Treatment with aldosterone does not affect the total lipid content of kidney or liver in adrenalectomized rats. The oxygen consumption rate of kidney cortex slices with lactate, beta-hydroxybuterate or acetoacetate as substrates is lowered after in vivo administration of aldosterone to adrenalectomized rats. With slccinate, however, the respiratory rate of kidney slices increases after aldosterone treatment of adrenalectomized rats, the ouabain-sensitive respiration being more affected than the ouabain-insensitive respiration. An interpretation of the O2 consumption data implicating competition of lipid metabolism for CoA-SH is discussed.

Acetoacetates↗

PubMed1986

Contraluminal transport of small aliphatic carboxylates in the proximal tubule of the rat kidney in situ.

In order to study the characteristic of contraluminal transport of hydrophylic small fatty acids the in situ stopped flow microperfusion technique [12] has been applied. By measuring with 4 s contact time the decrease in the contraluminal concentration of the respective radiolabelled substances the concentration dependence of the influx into the cortical cells was tested. The 4 s decrease in contraluminal concentration of chloroacetate, L-lactate, D-lactate, 3-hydroxybutyrate and acetoacetate was between 26% and 31%. For each substance the percent decrease was the same, no matter whether it was offered in a concentration of 0.1 or 10 mmol/l. Contraluminal disappearance of 0.1 mmol/l L-lactate was not influenced by 5 mmol/l H2DIDS, probenecid, phloretin, mersalyl or cyanocinnamate, but it was significantly (37%) inhibited by 5-nitro-2-(phenyl-propyl-amino) benzoate, a blocker of the nonspecific anion channel. The percent decrease in propionate uptake was somewhat larger - between 36% and 39% - but again not different at 0.01, 0.1, 1.0 and 10 mmol/l. With pyruvate the contraluminal decrease was 20% at 0.1 mmol/l and 31% at 10 mmol/l. The percent disappearance of the aromatic pyrazinoate was 38% and 34% at 0.1 and 10 mmol/l and for nicotinate 42% and 22%, respectively. The disappearance of nicotinate (0.1 mmol/l) was significantly inhibited by 10 mmol/l pyrazinoate and paraaminohippurate (PAH). The data are in agreement with the hypothesis that the hydrophilic small fatty acids traverse the contraluminal cell side by simple diffusion, possibly via the unspecific anion channel [14], pyruvate via the dicarboxylic acid pathway in a cooperative manner and pyrazinoate, as well as nicotinate, via the PAH pathway.

Acetates↗

PubMed1981

A comparative study of the transport of pyruvate in liver mitochondria from normal and diabetic rats.

A comparative study of the transport of pyruvate in liver mitochondria from normal and diabetic rats has been carried out. The Km for the pyruvate uptake in diabetic, ketotic mitochondria is practically equal to that measured in normal mitochondria, while the Vmax is significantly lower. The lower activity of the pyruvate translocator in diabetic mitochondria compared to normal mitochondria is also shown by swelling experiments as well as by following the rate of pyruvate-supported respiration. Pre-exposure of mitochondria from normal rats to the ketone body acetoacetate and to 2-oxobutyrate results in a decrease of the Km for pyruvate uptake. This effect is impaired in mitochondria from diabetic animals. The results indicate that the activity and the properties of the mitochondrial pyruvate translocator are modified in the diabetic, ketotic condition.

3-Hydroxybutyric Acid↗

PubMed1987

Mitochondrial pyruvate carrier--a possible link between gluconeogenesis and ketogenesis in the liver.

Effects of various ketogenic substrates on gluconeogenesis from lactate or alanine were compared. The results suggest that, in intact liver cells, cytoplasmic pyruvate is transported into mitochondria in exchange for intramitochondrially generated acetoacetate. An interrelationship between gluconeogenesis and ketogenesis may thus exist in the liver at the level of mitochondrial pyruvate carrier.

Acetoacetates↗

PubMed1975

[Serum lipoproteids and ketone bodies after constant infusion of sorbitol i.v. (author's transl)].

20 patients of a metabolic ward received a six-hour infusion of sorbitol at a dosis of 0.125 g/kg/h(n equal to 10) and 0.25 g/kg/h(n equal to 10) body weight. Cholesterol levels showed a significant fall in both groups (p smaller than 0.05) and triglycerides rose significantly (p smaller than 0.05). The concentrations of acetoacetate and beta-hydroxybutyrate were lowered irrespective of the dosis. The cholesterol-reducing effect can be explained by the antiketogenic action, whereas the increase in triglycerides possibly could be the result of raised alpha-glycerophosphate.

Acetoacetates↗

PubMed1982

[Regulation of ketone body levels before and following elective surgical operations during different intravenous feedings].

44 patients who had to undergo gastric resection and 28 patients who had to undergo cholecystectomy were divided into 4 groups each. Each group received parenterally a different energy source and calorie-nitrogen ratio. We intended to investigate the influence of different intravenous regimens on pre- and postoperative acetoacetate and beta-hydroxybutyrate levels. Patients undergoing gastric resection who received 0.36 g glucose/kg BW x h together with 1.14 g/kg BW x day 1-crystalline amino acids had the lowest postoperative ketone body concentration. A comparable group who received 0.36 g/kg BW x day of a carbohydrate-mixture solution consisting of glucose-fructose and xylitol in a proportion of 1:1:1 had significantly higher ketone bodies. The comparison of glucose with xylitol in a hypocaloric dosage of 0.11 g/kg BW x h led to a physiologic ketosis only in the group with xylitol as energy source from postoperative day 2 on. In patients undergoing cholecystectomy, the sole infusion of amino acids in a dosage of 1.14 g/kg BW x h led to the highest ketone bodies from the operation day on. The intravenous infusion of a polyol-mixture solution containing xylitol and sorbitol in a relation of 1:1 in a dosage of 4.2 g/kg BW x day led to the lowest ketone body production. The infusion of a polyol-mixture solution in a dosage of 2 g/kg BW x day enabled the development of a physiologic ketosis. In this study we could demonstrate that the infusion of xylitol or a polyol-mixture solution in a dosage of 2-3 g/kg BW x day after elective surgery enables the development of physiologic ketosis.

3-Hydroxybutyric Acid↗

PubMed1976

Modulation by ketone bodies of the rate of fatty acid synthesis in mammary gland slices from lactating rats.

The absolute rate of fatty acid synthesis was measured in slices of mammary gland from lactating rats by incubation in [3H]2O-labeled medium containing 10 mM D-3-hydroxybutyrate or acetoacetate alone and paired in combination with 10 mM glucose, lactate, or pyruvate. When compared with our previous studies, the ketone bodies alone supported significant fatty acid synthesis; the rate of synthesis from either ketone body and lactate was higher than that from pyruvate and lactate, and that from pyruvate and glucose; the rate of synthesis from D-3-hydroxybutyrate and lactate was the highest we have observed in the absence of an exogenous substrate for the hexose monophosphate pathway. This study confirms our previous contention that, in rat mammary gland, substrates formed in the mitochondria can be utilized in the cytosol to provide some of the NADPH necessary for fatty acid synthesis.

Acetoacetates↗