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PubMedDate not supplied

Glucosamine acetoacetate condensate. IV. Its effect upon diabetic mice.

Treatment with pyrrole condensate of obese diabetic mice, characterized by metabolic disturbances resembling diabetes mellitus in man, has resulted in the alleviation of classical diabetic symptoms, such as hyperglycemia, glycosuria, and low levels of liver glycogen.

Animals↗
PubMed1988

Pseudoketogenesis in the perfused rat heart.

Ketogenesis is usually measured in vivo by dilution of tracers of (3R)-hydroxybutyrate or acetoacetate. We show that, in perfused working rat hearts, the specific activities of (3R)-hydroxybutyrate and acetoacetate are diluted by isotopic exchanges in the absence of net ketogenesis. We call this process pseudoketogenesis. When hearts are perfused with buffer containing 2.3 mM of [4-3H]- plus [3-14C]acetoacetate, the specific activities of [4-3H] and [3-14C]acetoacetate decrease while C-1 of acetoacetate becomes progressively labeled with 14C. This is explained by the reversibility of reactions catalyzed by mitochondrial 3-oxoacid-CoA transferase and acetoacetyl-CoA thiolase. After activation of labeled acetoacetate, the specific activity of acetoacetyl-CoA is diluted by unlabeled acetoacetyl-CoA derived from endogenous fatty acids or glucose. Acetoacetyl-CoA thiolase partially exchanges 14C between C-1 and C-3 of acetoacetyl-CoA. Finally, 3-oxoacid-CoA transferase liberates weakly labeled acetoacetate which dilutes the specific activity of extracellular acetoacetate. An isotopic exchange in the reverse direction is observed when hearts are perfused with unlabeled acetoacetate plus [1-14C]-, [13-14C]-, or [15-14C]palmitate; here also, acetoacetate becomes labeled on C-1 and C-3. Computations of specific activities of (3R)-hydroxybutyrate, acetoacetate, and acetyl-CoA yield minimal rates of pseudoketogenesis ranging from 19 to 32% of the net uptake of (3R)-hydroxybutyrate plus acetoacetate by the heart.

3-Hydroxybutyric Acid↗
PubMed2000

Characterization of five catalytic activities associated with the NADPH:2-ketopropyl-coenzyme M [2-(2-ketopropylthio)ethanesulfonate] oxidoreductase/carboxylase of the Xanthobacter strain Py2 epoxide carboxylase system.

The bacterial metabolism of propylene proceeds by epoxidation to epoxypropane followed by carboxylation to acetoacetate. Epoxypropane carboxylation is a minimetabolic pathway that requires four enzymes, NADPH, NAD(+), and coenzyme M (CoM; 2-mercaptoethanesulfonate) and occurs with the overall reaction stoichiometry: epoxypropane + CO(2) + NADPH + NAD(+) + CoM --> acetoacetate + H(+) + NADP(+) + NADH + CoM. The terminal enzyme of the pathway is NADPH:2-ketopropyl-CoM [2-(2-ketopropylthio)ethanesulfonate] oxidoreductase/carboxylase (2-KPCC), an FAD-containing enzyme that is a member of the NADPH:disulfide oxidoreductase family of enzymes and that catalyzes the reductive cleavage and carboxylation of 2-ketopropyl-CoM to form acetoacetate and CoM according to the reaction: 2-ketopropyl-CoM + NADPH + CO(2) --> acetoacetate + NADP(+) + CoM. In the present work, 2-KPCC has been characterized with respect to the above reaction and four newly discovered partial reactions of relevance to the catalytic mechanism, and each of which requires the formation of a stabilized enolacetone intermediate. These four reactions are (1) NADPH-dependent cleavage and protonation of 2-ketopropyl-CoM to form NADP(+), CoM, and acetone, a reaction analogous to the physiological reaction but in which H(+) is the electrophile; (2) NADP(+)-dependent synthesis of 2-ketopropyl-CoM from CoM and acetoacetate, the reverse of the physiologically important forward reaction; (3) acetoacetate decarboxylation to form acetone and CO(2); and (4) acetoacetate/(14)CO(2) exchange to form (14)C(1)-acetoacetate and CO(2). Acetoacetate decarboxylation and (14)CO(2) exchange occurred independent of NADP(H) and CoM, demonstrating that these substrates are not central to the mechanism of enolate generation and stabilization. 2-KPCC did not uncouple NADPH oxidation or NADP(+) reduction from the reactions involving cleavage or formation of 2-ketopropyl-CoM. N-Ethylmaleimide inactivated the reactions forming/using 2-ketopropyl-CoM but did not inactivate acetoacetate decarboxylation or (14)CO(2) exchange reactions. The biochemical characterization of 2-KPCC and the associated five catalytic activities has allowed the formulation of an unprecedented mechanism of substrate activation and carboxylation that involves NADPH oxidation, a redox active disulfide, thiol-mediated reductive cleavage of a C-S thioether bond, the formation of a CoM:cysteine mixed disulfide, and enolacetone stabilization.

Acetoacetates↗
PubMed1977

Control of glucose metabolism in isolated acini of the lactating mammary gland of the rat. The ability of glycerol to mimic some of the effects of insulin.

Inhibition of glucose uptake by acetoacetate and relief of this inhibition by insulin found previously in slices of rat mammary gland [Williamson, McKeown & Ilic (1975) Biochem. J. 150. 145-152] was confirmed in acini, which represent a more homogeneous population of cells. Glycerol (1mM) behaved like insulin (50 minuits/ml) in its ability to relieve the inhibition of glucose (5 mM) utilization caused by acetoacetate (2 mM) in acini. Both glycerol and insulin reversed the increase in [citrate] and the decrease in [glycerol 3-phosphate] and the [lactate]/[pyruvate] ratio in the presence of acetoacetate. Lipogenesis from 3H2O, [3-14C] acetoacetate, [1-14C]- and [6-14C]-glucose was stimulated, whereas 14CO2 formation from [3-14C]acetoacetate was decreased. Neither insulin nor glycerol relieved the acetoacetate inhibition of glucose uptake when lipogenesis was inhibited by 5-(tetradecyloxy)-2-furoic acid. From measurements of [3-14C]acetoacetate incorporation into lipid in the various situations it is suggested that a cytosolic pathway for acetoacetate utilization may exist in rat mammary gland. In the absence of acetoacetate, glycerol inhibited glucose utilization by 60% and increased both [glycerol 3-phosphate] and the [lactate/[pyruvate] ratio. Possible ways in which glycerol may mimic the effects of insulin are discussed.

Acetoacetates↗
PubMed2002

Breath acetone is a reliable indicator of ketosis in adults consuming ketogenic meals.

BACKGROUND: Ketogenic diets are used therapeutically to treat intractable seizures. Clinically, it appears that the maintenance of ketosis is crucial to the efficacy of the diet in ameliorating seizures. To understand how ketosis and seizure protection are related, a reliable, noninvasive measure of ketosis that can be performed frequently with minimal discomfort is needed. OBJECTIVE: The objective was to determine which index, breath acetone or urinary acetoacetate, is more strongly related to the plasma ketones acetoacetate and beta-hydroxybutyrate. DESIGN: After fasting overnight for 12 h, 12 healthy adults consumed 4 ketogenic meals over 12 h. Blood, breath, and urine samples were collected hourly. Blood was analyzed for plasma acetoacetate and beta-hydroxybutyrate, breath for acetone, and urine for acetoacetate. RESULTS: By the end of the 12-h dietary treatment, plasma acetoacetate, plasma beta-hydroxybutyrate, and breath acetone had increased 3.5-fold, whereas urinary acetoacetate increased 13-fold when measured enzymatically and 25-fold when measured with urinary ketone dipsticks. Plasma acetoacetate was best predicted by breath acetone (R(2) = 0.70, P < 0.0001). Plasma beta-hydroxybutyrate was equally predicted by breath acetone and urinary acetoacetate (R(2) = 0.54, P = 0.0040). CONCLUSIONS: Breath acetone is as good a predictor of ketosis as is urinary acetoacetate. Breath acetone analysis is noninvasive and can be performed frequently with minimal discomfort to patients. As an indicator of ketosis in epilepsy patients consuming a ketogenic diet, breath acetone may be useful for understanding the mechanism of the diet, elucidating the importance of ketosis in seizure protection, and ultimately, enhancing the efficacy of the diet by improving patient monitoring.

3-Hydroxybutyric Acid↗
PubMed1990

Pseudoketogenesis in hepatectomized dogs.

Overestimation of ketone body turnover in vivo, measured by tracer kinetics, could occur if specific activity or molar percent enrichment is diluted in extrahepatic tissues by label exchange via reversal of 3-oxoacid-CoA transferase, a process we call pseudoketogenesis. To test this hypothesis, euglycemic hepatectomized dogs were injected with a bolus of acetoacetate (0.8 mmol/kg), 32% enriched in [3,4-13C2]acetoacetate. Concentrations and labeling patterns of blood acetoacetate and R-3-hydroxybutyrate were measured by selected ion-monitoring gas chromatography-mass spectrometry. During the 60 min after bolus injection of [3,4-13C2]acetoacetate, the molar percent enrichment of blood [3,4-13C2]acetoacetate decreased to 73 +/- 3% (n = 5) in controls and to 11.5 +/- 0.8% (n = 3) during infusion of dichloroacetate, an activator of pyruvate dehydrogenase. The enrichment of R-3-hydroxy-[3,4-13C2]butyrate followed closely that of [3,4-13C2]acetoacetate. These dilutions occurred despite a net uptake of ketone bodies. Concomitantly, 10.6 +/- 2.2 (n = 5) and 6.0 +/- 2.9% (n = 3) of [13C]acetoacetate molecules were labeled on all four carbons in control and dichloroacetate-treated dogs, respectively. This uniformly labeled acetoacetate arises from partial equilibration between [3,4-13C2]acetoacetate and [1,2-13C2]acetyl-CoA via the reactions catalyzed by 3-oxoacid-CoA transferase and acetoacetyl-CoA thiolase. Our data demonstrate the reversibility of the 3-oxoacid-CoA transferase in intact extrahepatic tissues and support the concept of pseudoketogenesis. This phenomenon has been quantitated by kinetic analysis of the data.

3-Hydroxybutyric Acid↗
PubMed1976

Blood D-3-hydroxybutyrate and the regulation of plasma concentrations of free fatty acids in the fasted rat.

Acetoacetate or DL-3-hydroxybutyrate were infused into fasted rats at rates comparable to the endogenous rate of ketone body release. Blood samples taken before and during infusion were analyzed for concentrations of ketone bodies, free fatty acids, and immunoreactive insulin. During infusion of acetoacetate or DL-3-hydroxybutyrate, blood concentrations of total ketone bodies doubled. While the HBA/AcAc ratios remained constant in rats infused with DL-3-hydroxybutyrate, the ratios decreased significantly during infusion of acetoacetate, reflecting increases in acetoacetate concentrations without proportionate increases in concentrations of D-3-hydroxybutyrate. Blood concentrations of free fatty acids decreased more rapidly in the rats infused with DL-3-hydroxybutyrate than in the rats infused with acetoacetate. The decrease in free fatty acid concentrations was related to increases in blood D-3-hydroxybutyrate in both the DL-3-hydroxybutyrate-infused rats and in the acetoacetate-infused rats. Plasma immunoreactive insulin concentrations were significantly higher in the DL-3-hydroxybutyrate-infused rats than in the acetoacetate-infused rats. Acetoacetate and DL-3-hydroxybutyrate were infused into depancreatized, functionally hepatectomized fasted rats at rates comparable to those used in the intact fasted rats. Only small decreases in free fatty acid concentrations were observed during infusion. From these experiments it was concluded that increases in blood concentrations of D-3-hydroxybutyrate were more effective than acetoacetate in causing decreases in free fatty acid concentrations in the fasting rat. The pancreas is required for this effect.

Animals↗
PubMed1981

Ketone bodies, glucose and glutamine as lipogenic precursors in human diploid fibroblasts.

Incorporation of [14C] from acetoacetate, D(-)- and L(+)-3-hydroxybutyrate, glucose, glutamine, acetate and palmitate in cellular lipids were studied in cultures in human diploid fibroblasts (HDF). The results showed that acetoacetate was 2-10 times more effective as a lipogenic precursor than was either D- or L-3-hydroxybutyrate. Its extent of incorporation into lipids was 2- to 8-fold more than the other precursors examined under conditions when the overall rates of nonsaponifiable and saponifiable lipogenesis as measured by 3H2O incorporation were essentially unchanged. Acetoacetate supported both saponifiable and nonsaponifiable lipid synthesis with half-saturation values (Km app.) of 185 microM and 30 microM, respectively. Glucose stimulated acetoacetate incorporation into lipids whereas, conversely, acetoacetate inhibited [14C]glucose incorporation into lipids. The presence of low density lipoproteins (LDL) cholesterol (40 microgram cholesterol/mL) inhibited the incorporation of [14C] from acetoacetate 56% into nonsaponifiable lipids; the inhibition was consistently higher (75%) when [14C]glucose or glutamine were the precursors. The loss of 3-hydroxy-3-methyl-glutaryl CoA (HMG CoA) reductase activity upon addition of LDL-cholesterol was greater than the suppression of [14C] incorporation from acetoacetate or glucose into nonsaponifiable lipids. In the presence of glucose, [14C]acetoacetate was incorporated into 3-beta OH sterols (digitonin precipitable) 7.7 +/- 1.1 times more effectively than was [14C]glucose. The results suggest that HDF would be a suitable model to investigate the effects of various precursors of HMG CoA on the rate of cholesterol biosynthesis.

3-Hydroxybutyric Acid↗
PubMed1988

Acute effects of the aldehyde dehydrogenase inhibitors, disulfiram, pargyline and cyanamide, on circulating ketone body levels in the rat.

Acetonemia is generally associated with the ketogenic states of fasting and diabetes. Disulfiram (DS), an inhibitor of aldehyde dehydrogenase (AlDH) that is used as an alcohol deterrent drug, is also known to elevate blood acetone in humans, but in the absence of a commensurate increase in its metabolic precursor, acetoacetate. We reexamined the effects of DS and other AlDH inhibitors on circulating ketone body levels in male rats of Sprague-Dawley descent and again demonstrated a 6- and 16-fold increase in blood acetone along with normal levels of acetoacetate at 6 and 24 hr after DS. Pargyline, another inhibitor of AlDH, maintained normal blood acetone levels in the presence of reduced acetoacetate levels. A third inhibitor of AlDH, cyanamide, administered to fasted and nonfasted rats, elevated blood acetone levels 10-fold over controls, with, however, a commensurate 5- and 7-fold increase in blood acetoacetate levels. The threshold values for the cyanamide-induced elevation of blood acetone and acetoacetate were equivalent, i.e. approximately 0.25 mmol/kg body weight (i.p.). The elevation of acetoacetate and the inhibition of hepatic catalase activity by cyanamide are not mechanistically linked, since 3-amino-1,2,4-triazole, another inhibitor of catalase, elevated blood acetone but not acetoacetate levels. These findings suggest that DS-induced acetonemia is due to inhibition of acetone metabolism, whereas enhanced acetone formation through acetoacetate contributes significantly to cyanamide-induced acetonemia.

3-Hydroxybutyric Acid↗
PubMed1975

Renal conservation of ketone bodies during starvation.

Renal handling of acetoacetate and beta-hydroxybutyrate was studied in 12 obese subjects undergoing total starvation. Simultaneously, the acetoacetate, beta-hydroxybutyrate, and inulin clearance rates were measured, and acetoacetate and beta-hydroxybutyrate reabsorption rates were calculated. Renal clearance of blood acetoacetate and beta-hydroxybutyrate remained constant. In contrast, acetoacetate reabsorption rate increased significantly from 47 plus or minus 10 mumoles/min on day 3 to 106 plus or minus 15, 89 plus or minus 10, and 96 plus or minus 10 mumoles/min on days 10, 17, and 24, respectively. Similarly, beta-hydroxybutyrate reabsorption rate increased significantly from 154 plus or minus 27 mumoles/min on day 3 to 419 plus or minus 53, 399 plus or minus 25, and 436 plus or minus 53 mumoles/min on days 10, 17, and 24, respectively. Both acetoacetate and beta-hydroxybutyrate reabsorption rates increased linearly when plotted against their filtered loads. Thus, no tubular maximal transport rate exists for acetoacetate or beta-hydroxybutyrate during physiologic ketonemia. Conservation 450-500 mmoles of ketone bodies/day prevents large urinary losses of cations during prolonged starvation. Since ammonium becomes the major cation excreted during prolonged fasting, the increased renal reabsorption of ketone bodies minimizes body protein loss and aids in maintaining high circulating acetoacetate and beta-hydroxybutyrate concentrations.

Acetoacetates↗
PubMed1968

The redox state of the nicotinamide-adenine dinucleotides in rat liver homogenates.

1. The redox state of the NAD couple of rat liver mitochondria, as measured by the [beta-hydroxybutyrate]/[acetoacetate] ratio, rapidly changed in the direction of oxidation during the preparation of homogenates in a saline medium. The value of the [beta-hydroxybutyrate]/[acetoacetate] ratio fell from 2.3 to 0.15 in 10min. EDTA diminished the fall and succinate prevented it. 2. The redox state of the rat liver cytoplasm, as measured by the [lactate]/[pyruvate] ratio, changed slightly in the direction of reduction during the preparation of homogenate. This was prevented by succinate. 3. In unsupplemented homogenates the differences in the redox states of mitochondria and cytoplasm decreased. Succinate and EDTA together maintained the differences within the physiological range. A measure of the ability of the mitochondria to maintain different redox states in mitochondria and cytoplasm is the value of the expression [lactate][acetoacetate]/[pyruvate][beta-hydroxybutyrate]. If there are no differences in the redox states of the NAD in the two cell compartments the value of the expression is 444 at 37 degrees . The value in the intact rat liver is between 4.7 and 21. 4. alpha-Oxoglutarate or glutamate were still more effective than succinate in maintaining high [beta-hydroxybutyrate]/[acetoacetate] ratios in the homogenates because these substrates supply a reducing agent of NAD(+) and, through succinate, an inhibitor of the oxidation of NADH. 5. When supplemented with alpha-oxoglutarate and EDTA, homogenates readily adjust the redox state of the beta-hydroxybutyrate dehydrogenase system after it has been upset by the addition of either acetoacetate or beta-hydroxybutyrate. 6. Amytal and rotenone raised the value of the [beta-hydroxybutyrate]/[acetoacetate] ratio. This is taken to indicate that the reduction of acetoacetate in the homogenates was not an energy-linked process. 7. 2,4-Dinitrophenol shifted the [beta-hydroxybutyrate]/[acetoacetate] ratio in the presence of succinate in favour of oxidation because it inhibited the oxidation of succinate and accelerated the oxidation of NADH. 8. Rotenone increased the rate of ketone-body formation of liver homogenates, though it decreased the rate of oxygen uptake.

Acetoacetates↗
PubMed1980

The nature of the calcium ion efflux induced in rat liver mitochondria by the oxidation of endogenous nicotinamide nucleotides.

Ca2+ efflux from rat liver mitochondria can occur when endogenous nicotinamide nucleotides are oxidized. It is suggested that nicotinamide nucleotide induced by acetoacetate sensitizes the mitochondria to damaage resulting from the accumulation of Ca2+ in the presence of Pi. Thus, acetoacetate-induced Ca2+ efflux is associated with a loss of respiratory control. Both the effluxes induced by acetoacetate and by high Ca2+ accumulation are prevented by ATP plus oligomycin, although these agents do not prevent the endoagenous nicotinamide nucleotides from becoming oxidized on addition of acetoacetate. Acetoacetate addition only results in Ca2+ release if the Ca2+ and Pi concentration are above a critical value. The acetoacetate-induced Ca2+ effflux is exactly paralled by the virtually complete collapse of the membrane potential. The presence of acetoacetate decreases the concentration of total Ca2+ necessary to induced mitochondrial damage by about 130 nmol of Ca2+/mg of protein. It is concluded that acetoacetate-induced efflux occurs by reversal of the Ca2+ uniporter after the collapse of the membrane potential.

Acetoacetates↗
PubMed2003

Distinct effects of ketone bodies on down-regulation of cell surface insulin receptor and insulin receptor substrate-1 phosphorylation in adrenal chromaffin cells.

Treatment (>/=24 h) of cultured bovine adrenal chromaffin cells with ketoacidosis-related concentrations (>/=3 mM) of acetoacetate (but not beta-hydroxybutyrate, acetone, and acidic medium) caused a time- and concentration-dependent reduction of cell surface (125)I-insulin binding by ~38%, with no change in the K(d) value. The reduction of (125)I-insulin binding returned to control nontreated level at 24 h after the washout of acetoacetate-treated cells. Acetoacetate did not increase the internalization rate of cell surface insulin receptor (IR), as measured in the presence of brefeldin A, an inhibitor of cell surface vesicular exit from the trans-Golgi network. Acetoacetate (10 mM for 24 h) lowered cellular levels of the immunoreactive IR precursor molecule (approximately 190 kDa) and IR by 22 and 28%, respectively. Acetoacetate decreased IR mRNA levels by approximately 23% as early as 6 h, producing their maximum plateau reduction at 12 and 24 h. The half-life of IR mRNA was shortened by acetoacetate from 13.6 to 9.5 h. Immunoprecipitation followed by immunoblot analysis revealed that insulin-induced (100 nM for 10 min) tyrosine-phosphorylation of insulin receptor substrate-1 (IRS-1) was attenuated by 56% in acetoacetate-treated cells, with no change in IRS-1 level. These results suggest that chronic treatment with acetoacetate selectively down-regulated the density of cell surface functional IR via lowering IR mRNA levels and IR synthesis, thereby retarding insulin-induced activation of IRS-1.

3-Hydroxybutyric Acid↗