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At least 19 recordsLinked to original sources

PubMed1978

Characterization of beta-hydroxybutyrate transport in rat erythrocytes and thymocytes.

A method was developed for study of beta-hydroxybutyrate transport in erythrocytes and thymocytes. Critical to the method was a centrifugal separation of cells from medium which took advantage of beta-hydroxybutyrate transport's temperature dependence and inhibition by phloretin and methylisobutylxanthine, all of which are demonstrated in this work. These properies suggested mediated transport, as did saturation kinetics and inhibition by several agents including pyruvate and alpha-cyanocinnamate. Most conclusive in this regard was a 2-fold preference for D- over L-beta-hydroxybutyrate. Entry was not Na+ dependent. It was stimulated by substitution of SO2-4 for most of the Cl-. The equilibrium beta-hydroxybutyrate space was much higher than the Cl- space of thymocytes, suggesting that beta-hydroxybutyrate entry is not associated with net inward negative current and is not coupled to outward Cl- or inward K+ movement (assuming that K+ is at elecrochemical equilibrium). Coupling to H+ entry or OH- exit is compatible with the result. These findings are consistent with beta-hydroxybutyrate entry by the carboxylate transport site which has been studied extensively with pyruvate and lactate as permeants. The Cl-/HCO-3 exchange carrier did not appear to contribute significantly to beta-hydroxybutyrate transport.

Animals↗

PubMed2025

Epigenetic Histone β-Hydroxybutyrylation Contributes to Renoprotection by β-Hydroxybutyrate in the Dahl Rat.

BACKGROUND: Previously, we demonstrated that the ketone body, β-hydroxybutyrate, is a potent antihypertensive and reno-protective metabolite in Dahl Salt-Sensitive rats. However, the mechanism by which β-hydroxybutyrate confers these beneficial effects is understudied. Here we focused on determining whether the reno-protective effect of β-hydroxybutyrate is due to its known ability to epigenetically remodel chromatin via histone β-hydroxybutyrylation. METHODS: We used the same animal protocol previously used for the discovery of the reno-protective effect of β-hydroxybutyrate. Briefly, postweaning, male and female Dahl Salt-Sensitive rats were split into 2 groups and supplemented with or without 1,3-butanediol for 6 weeks. At euthanasia, circulating β-hydroxybutyrate was quantitated. Renal homogenates were examined for histone 3 lysine 9 β-hydroxybutyrylation, chromatin occupancy, transcriptomic and proteomic profiles with validations. RESULTS: Rats supplemented with 1,3-butanediol had higher circulating β-hydroxybutyrate, renal histone β-hydroxybutyrylation, and significant remodeling of chromatin. Notably, regions of the genome associated with lipid catabolism were predominantly in an open chromatin configuration, leading to active transcription and translation. The most highly upregulated gene actively transcribed and translated was Hmgcs2 (3-hydroxy-3-methylglutaryl CoA synthase 2), a gene responsible for the biosynthesis of β-hydroxybutyrate in mitochondria. In contrast, regions with more compact chromatin structures contained immune function genes, Ptprc (protein tyrosine phosphatase receptor type C) and Lcp1 (lymphocyte cytosolic protein 1), which were suppressed. CONCLUSIONS: These results reveal that renal epigenetic histone β-hydroxybutyrylation is a novel mechanism by which transcriptional regulation of both energy metabolism and immune function occur concomitantly and contribute to renoprotection in the hypertensive Dahl rat.

Animals↗

PubMedDate not supplied

Chirality of the Hydrogen transfer to NAD catalyzed by (3R) hydroxybutyrate dehydrogenase from Pseudomonas lemoignei.

The chirality of the hydrogen transfer from (3R) hydroxybutyrate to NAD catalyzed by (3R)hydroxybutyrate dehydrogenase (E.C. 1.1.1.30, D-3-hydroxybutyrate : NAD oxidoreductase) from Pseudomonas lemoignei was investigated. [4(-3)H] NAD was enzymatically reduced to (4R) [4(-3)H]NADH with (3RS) hydroxybutyrate. This observation was confirmed since NAD could be reduced to (4S) [4(-3)H] NADH with (3RS) [3(-3)H] hydroxybutyrate and (3R) hydroxybutyrate dehydrogenase. From these experiments it can be concluded that (3R) hydroxybutyrate dehydrogenase from P. lemoignei should be classified as an B or (S) type dehydrogenase.

Hydroxybutyrate Dehydrogenase↗

PubMed1978

Effects of pH on beta-hydroxybutyrate transport in rat erythrocytes and thymocytes.

Entry of beta-hydroxybutyrate into erythrocytes and thymocytes is facilitated by a carrier (C), as judged from temperature dependence, saturation kinetics, stereospecificity, competition with lactate and pyruvate, and inhibition by moderate concentrations of methylisobutylxanthine, phloretin, or alpha-cyanocinnamate. We studied the dependence of influx and efflux on internal and external pH and [beta-hydroxybutyrate]. Lowering external pH from 8.0 to 7.3 to 6.6 enhanced influx into erythrocytes by lowering entry Km from 29 to 16 to 10 mM, entry V being independent of external pH. Lowering external pH inhibited efflux. At low external pH, external beta-hydroxybutyrate enhanced efflux slightly. At high external pH, external beta-hydroxybutyrate inhibited efflux. Internal acidification inhibited influx and internal alkalization enhanced influx. Internal beta-hydroxybutyrate (betaHB) enhanced influx more in acidified than alkalized cells. These data are compatible with coupled betaHB-/OH- exchange, betaHB- and OH- competing for influx, C:OH- moving faster than C: betaHB-, empty C being immobile. They are also compatible with coupled betaHB-/H+ copermeation, empty C moving inward faster than H+:C:betaHB-, H+:C being immobile, and C:betaHB- (without H+) being so unstable as not to be formed in significant amounts (relative to C, H+:C, and H+:C:betaHB-).

Animals↗

PubMed2025

Versatile sugar and valerate metabolic pathways in Paraburkholderia xenovorans LB400 enable tailored poly(3-hydroxybutyrate-co-3-hydroxyvalerate) production.

Poly(3-hydroxybutyrate) and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) polymers are accumulated by diverse prokaryotes. Their distinct monomer compositions enable their use as tailored bioplastics. The aims were to characterize the poly(3-hydroxybutyrate) and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) synthesis by Paraburkholderia xenovorans LB400 using different sugars and valerate, and to gain genome-oriented insights into polyhydroxyalkanoate production. d-Glucose, d-mannitol, d-gluconate, and d-xylose were evaluated as sole carbon sources or supplemented with valerate. Polyhydroxyalkanoates synthesized by strain LB400 were characterized through GC-MS, GC-FID, FTIR, and 1H and 13C-NMR. P. xenovorans LB400 reached 1.00-1.39 g L-1 of dry cell weight (DCW) with a P(3HB) content of 21-43% w w-1 when grown on different sugars. The addition of valerate to the sugar-grown LB400 cultures yielded a DCW of 1.79 to 2.29 g L-1 and a P(3HB-co-3HV) content of 50.0‒51.2% w w-1, with varying 3HV compositions (28‒43 mol%). The highest 3HV incorporation was observed with d-xylose and valerate. Genomic analyses of strain LB400 revealed key elements of sugar metabolism influencing growth, polymer accumulation, and monomer composition. LB400 genome encodes the PhaJ-like R-specific hydratase and FadJ epimerase, which are potentially useful for modulating copolymer composition. PHA production under bioreactor conditions was evaluated. In a bioreactor fed with d-glucose, LB400 achieved a P(3HB) concentration of 2.2 g L-1. These findings highlight the metabolic versatility of P. xenovorans LB400 in utilizing diverse sugars to produce either P(3HB) or tailor-made P(3HB-co-3HV), supporting the development of bioplastics for specific applications. KEY POINTS: • Strain LB400 produced P(3HB-co-3HV) from various sugars and valerate. • Sugar type drives LB400 PHA copolymer synthesis and composition. • Strain LB400 PHA production was scaled up to a bioreactor.

Polyesters↗

PubMed1978

Utilization of 3-hydroxybutyrate by chick cerebral hemispheres during postnatal maturation.

1. The utilization of 3-hydroxybutyrate has been studied in the chick telencephalon during its post-hatching maturation. 2. In the 1-day-old chick the blood concentration of 3-hydroxybutyrate appears to be relatively high and its value is 5 times that estimated in the 4- and 30-day-old chicks. 3. The determination of the cerebral arteriovenous differences of 3-hydroxybutyrate shows that the brain of the newly-hatched chick takes up 3 times more actively this ketone body than the brain of the 4-day-old bird does. 4. During incubation in a non-oxygenated and an oxygenated physiological medium, in the presence of 3-hydroxy [3-14C]butyrate, the specific radioactivity of the dicarboxylic amino acids in the 1-day-old chick brain slices is higher than in those of the 30-day-old chick, particularly in the oxygenated medium. 5. Thirty minutes after a subcutaneous injection of 3-hydroxy [3-14C]butyrate, the specific radioactivity of the dicarboxylic amino acids in the 1-day-old chick telencephalon is 3-4 times higher than that in the 4- and 30-day-old chick. 6. In conclusion, in the brain of the newly hatched chick, 3-hydroxybutyrate is an efficient precursor in the biosynthesis of dicarboxylic amino acids, particularly glutamate, and, as glucose, it is metabolically related to the "large compartment" of glutamate. 7. These results have been discussed comparatively to those previously obtained in the developing rodent brain.

3-Hydroxybutyric Acid↗

PubMed1975

Possible occurrence for histidyl and cysteyl residues in the catalytic center of rat liver mitochondrial D (-)-beta-hydroxybutyrate dehydrogenase.

1. Rat liver mitochondrial D(-)-beta-hydroxybutyrate dehydrogenase (submitochondrial particles and partially purified preparation) is inhibited by some dicarboxylates, especially by malonate and succinate. The inhibition is reversible and competitive with beta-hydroxybutyrate while uncompetitive with acetoacetate, NAD and NADH: the inhibition is maximal at pH 6 and decrease with increasing pH. 2. Diethylpyrocarbonate (which reacts preferentially with histidyl residues at pH 6.6) inactivates the dehydrogenase at pH 6.1, beta-hydroxybutyrate protects against inactivation, this inactivation being almost completely released by hydroxylamine. The diethylpyrocarbonate-treated enzyme shows an absorbance increase at 242 nm which is characterisitic of reaction between diethylpyrocarbonate and histidyl residue. 3. The optimum pH of the enzyme for beta-hydroxybutyrate oxidation is around 8.2, while for acetoacetate reduction, the optimum pH is around 7. 4. All these results favour the existence of a histidyl residue in the catalytic center and taking into account previous results concerning the effect of thiol reagents on the same enzyme and especially, the protective effect of NAD+ and NADH against these reagents [11] we discuss the possible occurrence of, at least, one histidyl and one cysteyl residue on the catalytic center.

Acetoacetates↗

PubMed1976

Acetyl-CoA production and utilization during growth of the facultative methylotroph Pseudomonas AM1 on ethanol, malonate and 3-hydroxybutyrate.

In Pseudomonas AM1, conversion of 3-hydroxybutyrate to acetyl-CoA is mediated by an inducible 3-hydroxybutyrate dehydrogenase, an acetoacetate: succinate coenzyme A transferase (specific for succinyl-CoA) and an inducible beta-ketothiolase. Ethanol is oxidized to acetate by the same enzymes as are involved in methanol oxidation to formate. An inducible acetyl-CoA synthetase has been partially purified and characterized; it is essential for growth only on ethanol, malonate and acetate plus glyoxylate, as shown by the growth characteristics of a mutant (ICT54) lacking this enzyme. Free acetate is not involved in the assimilation of acetyl-CoA, and hydroxypyruvate reductase is not involved in the oxidation of acetyl-CoA to glyoxylate during growth on 3-hydroxybutyrate. A mutant (ICT51), lacking 'malate synthase' activity has been isolated and its characteristics indicate that this activity is normally essential for growth, of Pseudomonas AM1 on ethanol, malonate and 3-hydroxybutyrate, but not for growth on other substrates such as pyruvate, succinate and C1 compounds. The growth properties of a revertant (ICT51R) and of a mutant lacking malyl-CoA lyase (PCT57) indicate that an alternative route must exist for assimilation of compounds metabolized exclusively by way of acetyl-CoA.

Acetate-CoA Ligase↗

PubMed1976

Inhibition of adenosine 3':k'-monophosphate accumulation white fat acids, lactate, and beta-hydroxybutyrate.

The large increase in cyclic AMP accumulation by rat white fat cells seen in the presence of lipolytic agents plus methylxanthines and adenosine deaminase was markedly inhibited by lactate. However, lipolysis was unaffected by lactate. Octanoate, hexanoate, heptanoate, and beta-hydroxybutyrate inhibited both cyclic AMP accumulation and lipolysis by rat fat cells. The mechanism by which these acids inhibit lipolysis differs from that for long chain fatty acids such as oleate. Oleate directly inhibited triglyceride lipase activity of homogenized rat adipose tissue. In contrast, octanoate, beta-hydroxybutyrate, and lacatate had no effect on triglyceride lipase activity. Hormone-stimulated adenylate cyclase activity of rat fat cell ghosts was inhibited by oleate and 4mM octanoate but not by 1.6 mM octanoate, heptanoate, hexanoate, beta-hydroxybutyrate or lactate. None of the acids affected the soluble protein kinase activity of rat adipose tissue. There was no stimulation by lactate, butyrate, beta-hydroxybutyrate, or octanoate of the soluble or particulate cyclic AMP antilipolytic action of a short chain acid such as octanoate or hexanoate was not accompanied by any drop in total fat cell ATP. The mechanism by which lactate lowers cyclic AMP but not lipolysis remains to be established.

Adenylyl Cyclases↗

PubMed1978

Variations of D (-)-beta-hydroxybutyrate dehydrogenase activity of rat liver mitochondria during post-natal development.

1. D(-)-beta-hydroxybutyrate dehydrogenase specific activity of rat liver mitochondria changes during ontogenesis: at birth, the activity is low, then increases to a maximum at 12 days, decreases until 50 days to keep constant thereafter. At the same time, mitochondrial protein amount increases regularly while succinatecytochrome c reductase specific activity slightly increases after birth to keep constant afterwards. 2. The observed changes in activity of D(-)-beta-hydroxybutyrate dehydrogenase are not related to possible interactions between the enzyme and phospholids since addition of lecithin to mitochondria does not change the activity. 3. Electrophoresis of mitochondrial proteins isolated from rats at different development stages demonstrates the presence of a protein band characterized by the same electrophoretic mobility as beta-hydroxybutyrate dehydrogenase and by significative changes of its proportion during maturation: the relative amount of this protein increases from the new-born to the 10-12 days old rat, to decrease afterwards. 4. These findings may signify that the increased activity of the enzyme with a maximum at 10-12 days followed by a decrease is related to the rate of the enzymes biosynthesis.

Aging↗

PubMed1978

Purification and properties of beta-hydroxybutyrate dehydrogenase from Mycobacterium phlei ATCC354.

beta-Hydroxybutyrate dehydrogenase (EC 1.1.1.30) was purified 145-fold from Mycobacterium phlei ATCC354 by ammonium sulphate fractionation and DEAE-cellulose chromatography. The pH optima for oxidation and reduction reactions were 8.4 and 6.8 respectively. The purified enzyme was specific for NAD, NADH, acetoacetate and D(-)-beta-hydroxybutyrate. Km values for DL-beta-hydroxybutyrate and NAD were 7.4 mM and 0.66 mM respectively. The enzyme was inactivated by mercurial thiol inhibitors and by heat, but could be protected by NADH, Ca2+ and partially by Mn2+. The enzyme did not require metal ions and was insensitive to EDTA, glutathione, dithiothreitol, beta-mercaptoethanol and cysteine.

Chloromercuribenzoates↗

PubMed1979

Specific methods for the determination of radioactivity in D-(-)-3-hydroxybutyrate in blood plasma.

Two simple, high-yield rapid methods with good reproducibility are described, which permit the determination of radioactivity in plasma D-(-)-3-hydroxybutyrate. The compound is converted to acetoacetate, using a modified enzymatic method. In procedure 1, acetoacetate is reacted with 2,4-dinitrophenylhydrazine; the resulting hydrazone is oxidised by means of a sample oxidiser, and the product 14CO2 is collected in scintillation liquid and counted. In procedure 2, a Conway microdiffusion unit is applied. The acetoacetate is decarboxylated to acetone in the presence of o-phenylenediamine, and the acetone is then diffused into semicarbazide solution. This solution, containing the semicarbazone derivative of labelled acetone, is transferred to liquid scintillation and counted. In both procedures the radioactivity is measured simultaneously in a separate sample which was not subjected to the enzymatic conversion of D-(-)-3-hydroxybutyrate. The difference in radioactivity between the two samples is attributed to labelled (D-(-)-3-hydroxybutyrate.

Carbon Radioisotopes↗

PubMed1975

Extraction of D-beta-hydroxybutyrate by brain in diabetic rats.

Statistically significant cerebral arteriovenous differences of D-beta-hydroxybutyrate were found in rats made diabetic by administration of streptozotocin. The amount of D-beta-hydroxybutyrate extracted by the brain in diabetic animals increased with increasing arterial concentrations and the extraction ratios were comparable to those found in animals and humans with ketosis due to other causes.

Animals↗

PubMed1975

The formation of 2-hydroxybutyric acid in experimental animals.

1. The formation of 2-hydroxybutyric acid (2-HB) has been studied by animal experiments. 2. 2-HB was excreted in the urine together with lactic acid following intravenous administration of huge amounts of 3-hydroxybutyric acid (sodium salt) to a dog. 3. Rats made diabetic by an injection of streptozotocin were found to excrete large quantities of 2HB in the urine (up to 300 mumol/24 h) together with the development of ketoacidosis. 4. The use of 14-C-labelled precursors clearly showed that the amino acids methionine, threonine and homoserine can be converted to 2-HB. 5. 2-Aminobutyric acid is also converted to 2-HB, with 2-oxobutyric acid as an intermediate metabolite. The ratio between the urinary concentrations of 2-HB and 2-oxobutyric acid was increased by the ingestion of ethanol. 6. In normal rats neither a prolonged fasting period nor loading with large doses of methionine, threonine and homoserine resulted in the excretion of 2-HB. 7. The mechanisms behind the formation of 2-HB are discussed, and it is concluded that an increased NADH2/NAD ratio in the cytoplasma is the most important factor.

Amino Acids↗

PubMed1976

Determination of isoenzyme contents of lactic dehydrogenase activity and 2-hydroxybutyric dehydrogenase activity in lactic dehydrogenase preparations.

In this inestigation, a determination of the isoenzyme contents of LDH and HBD activities in lactate dehydrogenase preparations and the differences in the interaction of these preparations with NAD analogues were examined. The results obtained were as follows. 1. The activity ratio between oxidation and reduction in LDH reaction is shown to be similar in both H4 and M4 preparations, whereas for HBD activity, the ratio seems to be lower in the M4 preparation than in H4(H4/M = 1/2). 2. NAD and its analogues (NXD, TNAD, and TNXD) are shown to be useful coenzymes for the LDH reaction, while 3-acetyl derivatives appear to be unsuitable for this purpose because of their lower activity. HBD activity with 3-acetyl NXD is shown to be higher than with TNAD or TNXD. among these NAD analogues, 3-acetyl NXD gives the highest HBD activity, especially in the M4 preparation. 3. The LDH activity of H4 relative to M4 preparations has been shown to be maximal when 450 mM lactic acid with NAD or 15 mM lactic acid with TNXD are used. Under these conditions, the contents of LDH subunits can be estimated with considerable reliability. As to HBD activity, the content of LDH subunit having HBD activity has been estimated by determing the enzyme activity under conditions in which either 300 mM 2-hydroxybutyrate with 3-acetyl NXD or 15 mM 2-hydroxybutyrate with NAD are employed.

Hepatitis↗

PubMed1976

Regulation of the tricarboxylic acid cycle and poly-beta-hydroxybutyrate metabolism in Azotobacter beijerinckii grown under nitrogen or oxygen limitation.

Azotobacter beijerinckii was grown in ammonia-free glucose/mineral salts media in chemostat culture under oxygen or nitrogen limitation. Selected enzymes of the tricarboxylic acid cycle and poly-beta-hydroxybutyrate metabolism were monitored in relation to oxygen supply for both steady and transition states. Two dissolved oxygen concentrations were used for the nitrogen-limited steady state to investigate the possible effects of respiratory protection of nitrogenase on these enzymes. The levels of NADH oxidase, isocitrate dehydrogenase and 2-oxoglutarate dehydrogenase increased markedly on relaxation of oxygen limitation while pyruvate dehydrogenase and citrate synthase were relatively unaffected. beta-Ketothiolase and acetoacetyl-CoA reductase levels decreased as oxygen limitation was relaxed. Respiratory activity, as measured by the QO2 value, increased with oxygen supply rate. Imposition of oxygen limitation on a nitrogen-limited culture caused an immediate increase in the NADH/NAD ratio but this rapidly readjusted to its previous steady-state value. These changes are discussed in relation to respiratory protection of nitrogenase and poly-beta-hydroxybutyrate metabolism in A. beijerinckii.

Acetyl-CoA C-Acetyltransferase↗

PubMed1977

Fasting plasma levels of glucose, acetoacetate, D-beta-hydroxybutyrate, glycerol, and lactate in the baboon infant: correlation with cerebral uptake of substrates and oxygen.

The energy-rich substrates available to the fasting stressed baboon neonate and infant are quantitatively similar to the metabolic fuels presented to the stressed low birth weight human newborn. Within a few hours after birth, fasting arterial plasma glucose levels in the baboon neonate approximate those of 4-6-week-old baboon infants after a 20-hr fast. Lactate levels are high and comparable for both age groups. In contrast, beta-hydroxybutyrate is quite low in the immediate neonatal period, but rises to significantly higher levels (P less than 0.001) after a fast at 4-6 weeks. In addition, glycerol levels are higher (P less than 0.02) in the fasted older infant compared with the fasting neonate. Computation of mean cerebral blood arteriovenous differences and oxygen equivalents for animals studied in the first 50 hr of life demonstrates that glucose uptake can account for 50% or less of cerebral oxygen consumption in the newborn period. In confirmation, the respiratory quotient in these animals is 0.52 +/- 0.06. Cerebral oxygen consumption in the immediate neonate is greater than can be explained by utilization of glucose and the small quantities of acetoacetate and beta-hydroxybutyrate available at this time. At birth, cerebral uptake of lactate is noted, but this phenomenon is not observed at 6 and 12 weeks of age.

Acetoacetates↗

PubMed1978

Gamma hydroxybutyrate in the monkey. I. Electroencephalographic, behavioral, and pharmacokinetic studies.

Gamma hydroxybutyrate (GHB) was administered to adult and prepubescent rhesus monkeys intravenously in varying dosages while an electroencephalogram (EEG) was recorded from scalp electrodes and the body core temperature was monitored. Blood and cerebrospinal fluid samples were assayed for gamma hydroxybutyrate. GHB produced a trancelike stupor in all the monkeys, associated with marked EEG changes and hypothermia. There was a striking age specificity in that prepubescent rhesus monkeys responded to a lower threshold dosage, had a higher incidence of myoclonic jerking, and showed characteristic EEG changes not seen in the adult animals. The EEG-behavioral changes paralleled the hypothermia. There was good correlation between the serum levels of GHB and the EEG-behavioral effects. These studies suggest that the GHB-treated monkey may have utility as a petit mal seizure model.

Animals↗