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PubMed1982

Role of pyruvate transporter in the regulation of the pyruvate dehydrogenase multienzyme complex in perfused rat liver.

Metabolic substrates such as octanoate, beta-hydroxybutyrate, and alpha-ketoisocaproate which produce acetoacetate stimulate the rate of pyruvate decarboxylation in perfused livers from fed rats at perfusate pyruvate concentrations in the physiological range (below 0.2 mM). A quantitative relationship between pyruvate oxidation (14CO2 production from [1-14C]pyruvate) and ketogenesis (production of acetoacetate or total ketone bodies) was observed with all ketogenic substrates when studied over a wide range of concentrations. The ratio of extra pyruvate decarboxylated to extra acetoacetate produced was greater than 1 with octanoate and alpha-ketoisocaproate, but it was less than 1 with beta-hydroxybutyrate. The stimulatory effect of beta-hydroxybutyrate on pyruvate decarboxylation was abolished completely in the presence of 0.1 mM alpha-cyanocinnamate, an inhibitor of the pyruvate transporting system in the mitochondrial membrane. The data suggest that the mechanism by which the flux through the pyruvate dehydrogenase reaction is stimulated in liver under ketogenic conditions involves an acceleration of the net rate of pyruvate transport into the mitochondria compartment due to an exchange with acetoacetate and/or acetoacetate plus beta-hydroxybutyrate.

Acetoacetates↗
PubMed1969

Rates of ketone-body formation in the perfused rat liver.

1. The rates of formation of acetoacetate and beta-hydroxybutyrate by the isolated perfused rat liver were measured under various conditions. 2. The rates found after addition of butyrate, octanoate, oleate and linoleate were about 100mumoles/hr./g. wet wt. in the liver of starved rats. These rates are much higher than those found with rat liver slices. 3. The differences between the rates given by slices and by the perfused organ were much higher with the long-chain than with short-chain fatty acids. The increments caused by oleate and linoleate were 12 and 16 times as large in the perfused organ as in the slices, whereas the increments caused by butyrate and octanoate were about four times as large. 4. The rates of ketogenesis in the unsupplemented perfused liver of well-fed rats, and the increments caused by the addition of fatty acids, were about half of those in the liver from starved rats. 5. The value of the [beta-hydroxybutyrate]/[acetoacetate] ratio of the medium was raised by octanoate, oleate and linoleate. 6. Carnitine did not significantly accelerate ketogenesis from fatty acids. 7. Oleate formed up to 82% of the expected yield of ketone bodies. 8. In the liver of alloxan-diabetic rats the endogenous rates of ketogenesis were raised, in some cases as high as in the liver from starved rats, after addition of oleate. 9. On addition of either beta-hydroxybutyrate or acetoacetate to the perfusion medium the liver gradually adjusted the [beta-hydroxybutyrate]/[acetoacetate] ratio towards the normal range. 10. The [beta-hydroxybutyrate]/[acetoacetate] ratio of the medium was about 0.4 when slices were incubated, but near the physiological value of 2 when the liver was perfused. 11. The experiments demonstrate that for the study of ketogenesis slices are in many ways grossly inferior to the perfused liver.

Acetoacetates↗
PubMed1980

Effect of carnitine on mitochondrial oxidation of palmitoylearnitine.

The effects of carnitine on the metabolism of palmitoylcarnitine were studied by using isolated rat liver mitochondria. Particular attention was given to carnitine acyltransferase-mediated interactions between carnitine and the mitochondrial CoA pool. Carnitine concentrations less than 1.25mm resulted in an increased production of acetylcarnitine during palmitoylcarnitine oxidation. Despite this shunting of C(2) units to acetylcarnitine formation, no change was observed in the rate of oxygen consumption or major product formation (citrate or acetoacetate). Further, no changes were observed in the mitochondrial content of acetyl-CoA, total acid-soluble CoA or acid-insoluble acyl-CoA. These observations support the concept, based on studies in vivo, that the carnitine/acylcarnitine pool is metabolically sluggish and the acyl-group flux low as compared with the CoA/acyl-CoA pool. Acid-insoluble acyl-CoA content was decreased and CoA content increased at carnitine concentrations greater than 1.25mm. When [(14)C]carnitine was used in the incubations, it was demonstrated that this resulted from acid-insoluble acylcarnitine formation from intramitochondrial acid-insoluble acyl-CoA mediated by carnitine palmitoyltransferase B. Again, the higher carnitine concentrations resulted in no changes in the rates of oxygen consumption or major product formation. The above effects of carnitine were observed whether citrate or acetoacetate was the major product of oxidation. In contrast, an increase in acetyl-CoA concentration was observed at high carnitine concentrations only when acetoacetate was the product. Since the rate of acetoacetate production was not changed, these higher acetyl-CoA concentrations suggest that a new steady state had been established to maintain acetoacetate-production rates. Since there was no change in acetyl-CoA concentration when citrate was the major product, a change in the activity of the pathway utilizing acetyl-CoA for ketone-body synthesis and the potential regulation of this pathway must be considered.

Acetoacetates↗
PubMed1981

Regulation of acetoacetyl-CoA in isolated perfused rat hearts.

The role of ketone bodies and long-chain fatty acids in regulating myocardial content of acetoacetyl-CoA was examined in isolated perfused hearts from fed rats. Addition of 10 mM acetoacetate to a perfusion medium containing 5.5 mM glucose as exogenous substrate resulted in a sevenfold increase of cardiac acetoacetyl-CoA content. Inclusion of 0.75--0.94 mM palmitate in the perfusate did not augment the basal level of acetoacetyl-CoA nor did it influence the already elevated content of the metabolic intermediate shown to exist in the presence of acetoacetate alone. In addition to the observed increase in myocardial acetoacetyl-CoA, a decrease in free carnitine in hearts perfused with acetoacetate was accompanied by elevated ratios of both acetylcarnitine/carnitine and long-chain fatty acylcarnitine/carnitine. Addition of palmitate in the presence of acetoacetate resulted in a further diminution of myocardial free carnitine leading to a further elevation of the long-chain fatty acylcarnitine/carnitine ratio when compared to hearts perfused with the ketone body alone. The changes in myocardial CoA and carnitine and their intermediates in hearts perfused with acetoacetate either alone or in combination with palmitate indicate that ketone bodies can divert fatty acids away from oxidation and toward esterification as triacylglycerols. Even though the interrelationships between ketones and myocardial fatty acid metabolism have not been fully characterized, a role for ketone bodies in promoting the increase in myocardial acetoacetyl-CoA found in diabetic ketoacidosis has been clearly defined.

Acetoacetates↗
PubMed1991

Fatty acid oxidation and ketogenesis by astrocytes in primary culture.

The oxidation of the fatty acids octanoate and palmitate to CO2 and the ketone bodies acetoacetate and D-(-)-3-hydroxybutyrate was examined in astrocytes that were prepared from cortex of 2-day-old rat brain and grown in primary culture to confluence. Accumulation of acetoacetate (by mass) in the culture medium of astrocytes incubated with octanoate (0.3-0.5 mM) was 50-90 nmol C2 units h-1 mg of protein-1. A similar rate was obtained using radiolabeled tracer methodology with [1-14C]octanoate as labeled substrate. The results from the radiolabeled tracer studies using [1-14C]- and [7-14C]octanoate and [1-14C]-, [13-14C]-, and [15-14C]palmitate indicated that a substantial proportion of the omega-terminal four-carbon unit of these fatty acids bypassed the beta-ketothiolase step of the beta-oxidation pathway and the 3-hydroxy-3-methylglutaryl (HMG)-CoA cycle of the classic ketogenic pathway. The [14C]acetoacetate formed from the 1-14C-labeled fatty acids, obligated to pass through the acetyl-CoA pool, contained 50% of the label at carbon 3 and 50% at carbon 1. By contrast, the [14C]acetoacetate formed from (omega-1)-labeled fatty acids contained 90% of the label at carbon 3 and 10% at carbon 1, whereas that formed from the (omega-3)-labeled fatty acid contained 20% of the label at carbon 3 and 80% at carbon 1. These results indicate that acetoacetate is primarily formed either by the action of 3-oxo-acid-CoA transferase (EC 2.8.3.5) or acetoacetyl-CoA deacylase (EC 3.1.2.11) or both on acetoacetyl-CoA and not by the action of the mitochondrial HMG-CoA cycle involving HMG-CoA lyase (EC 4.1.3.4), which was readily detected, and HMG-CoA synthase (EC 4.1.3.5), which was barely measurable.

Acetoacetates↗
PubMed1972

Rapid blood ketone body estimation in the diagnosis of diabetic ketoacidosis.

Different methods of assessing ketone body concentrations in blood and plasma of ketoacidotic patients have been compared. We confirmed that Ketostix reacts strongly with acetoacetate, giving a useful range of 0 to 10 mM for plasma acetoacetate, that acetone reacts weakly, and that 3-hydroxybutyrate does not react at all. Plasma Ketostix readings correlated only moderately well with enzymatically determined whole-blood acetoacetate. All samples giving a + + + reaction contained more than 1.6 mM acetoacetate while only 4 out of 21 samples showing 0 contained more than 0.4 mM. Comparison of Ketostix readings with total blood ketone body content showed poor correlation. One reason for this was the large variation in the ratio of 3-hydroxybutyrate to acetoacetate in ketoacidosis; another was that often Ketostix had been stored in such a way that they had become damp, which impairs their reliability. If the Ketostix reading and estimation of the blood pH show a discrepancy we suggest that an enzymatic assay should be used to determine the ketone bodies and lactate.

Acetoacetates↗
PubMed1971

Human forearm metabolism during progressive starvation.

Forearm muscle metabolism was studied in eight obese subjects after an overnight, 3 and 24 day fast. Arterio-deep-venous differences of oxygen, carbon dioxide, glucose, lactate, pyruvate, free fatty acids, acetoacetate, and beta-hydroxybutyrate with simultaneous forearm blood flow were measured. Rates of metabolite utilization and production were thus estimated. Oxygen consumption and lactate and pyruvate production remained relatively constant at each fasting period. Glucose, initially the major substrate consumed, showed decreased consumption after 3 and 24 days of fasting. Acetoacetate and beta-hydroxybutyrate consumption after an overnight fast was low. At 3 days of fasting with increased arterial concentrations of acetoactate and beta-hydroxybutyrate, consumption of these substrates rose dramatically. At 24 days of fasting, despite further elevation of arterial levels of acetoacetate and beta-hydroxybutyrate, the utilization of acetoacetate did not increase further and if anything decreased, while five out of eight subjects released beta-hydroxybutyrate across the forearm. Acetoacetate was preferentially extracted over beta-hydroxybutyrate. At 24 days of starvation, free fatty acids were the principal fuels extracted by forearm muscle; at this time there was a decreased glucose and also ketone-body consumption by skeletal muscle.

Acetoacetates↗
PubMed1976

Ketonemia and seizures: metabolic and anticonvulsant effects of two ketogenic diets in childhood epilepsy.

Metabolic effects of a new ketogenic regimen in which ketonemia is induced by feeding of medium chain triglycerides (MCT) are described, and comparisons are made with effects of the standard high fat ketogenic diet. Eighteen children maintained on the MCT diet for 3 months to 4 years failed to show elevations of serum cholesterol and had only a slight rise in serum total fatty acids, in contrast to the marked hyperlipidemia observed in children on the standard high fat diet. Long term use of the MCT diet did not affect pH of venous blood. Blood glucose fell below 50 mg/100 ml in one-third of the children, the lowest levels being reached 2--3 weeks after the start of the diet. Plasma D(--)-beta-hydroxybutyrate (BHB) and acetoacetate rose gradually after institution of diet therapy, maximum levels being reached after about 1 month. Higher levels of BHB and acetoacetate were achieved in children under the age of 10 years (BHB = 4.3 mM +/- 0.6 SEM, acetoacetate = 1.8 mM +/- 0.3 SEM) than in 10--18 year olds (BHB = 1.6 mM +/- 0.2 SEM, acetoacetate = 0.57 mM +/- 0.08 SEM). Plasma BHB and acetoacetate levels in children maintained on a 3:1 high fat diet were similar to those in children on a 60% MCT diet. Plasma levels of BHB showed a significant correlation with anticonvulsant effect (P less than 0.02). Both the ketonemia and the anticonvulsant action were reversed rapidly by intravenous infusion of glucose.

Acetoacetates↗
PubMed1986

Effects of ketone bodies on basal and insulin-stimulated glucose utilization in man.

Using the euglycemic clamp technique, we investigated the effects of high ketone body levels on basal and insulin-stimulated glucose utilization in normal subjects. Infusion of sodium acetoacetate in the postabsorptive state raised ketone body levels from 150 +/- 20 (+/- SE) mumol/liter to more than 1 mmol/liter. Endogenous glucose production declined from 2.71 +/- 0.20 mg kg-1 min-1 to 1.75 + 0.26 (P less than 0.01) and glucose utilization from 2.71 +/- 0.20 to 1.98 +/- 0.17 mg kg-1 min-1 (P less than 0.01), while blood glucose was maintained at the initial level by the infusion of glucose. There were no changes in plasma glucagon, insulin, or C-peptide. Plasma nonesterified fatty acids (P less than 0.01) and blood glycerol (P less than 0.01) and alanine (P less than 0.05) decreased, while blood lactate increased (P less than 0.01). Infusion of sodium bicarbonate had no effect on glucose kinetics. The decreases in glucose utilization and endogenous glucose production during the infusion of acetoacetate were not modified when the fall of plasma nonesterified fatty acids was prevented by iv heparin injection. During control euglycemic hyperinsulinemic clamps (1 and 10 mU kg-1 min-1 insulin infusion), endogenous glucose production was suppressed at the lowest insulin infusion rate; glucose utilization increased first to 7.32 +/- 0.96 mg kg-1 min-1 and then to 16.5 +/- 1.27 mg kg-1 min-1. During euglycemic hyperinsulinemic clamps with simultaneous sodium acetoacetate infusion, similar insulin levels were attained; endogenous glucose production was also suppressed at the lowest insulin infusion rate, and insulin-stimulated glucose utilization rates (7.93 +/- 1.70 and 15.80 +/- 1.30 mg kg-1 min-1) were not modified. In conclusion, acetoacetate infusion decreased basal, but not insulin-stimulated, glucose utilization. The increase in lactate during acetoacetate infusion in the postabsorptive state suggests that ketone body acted by decreasing pyruvate oxidation.

Acetoacetates↗
PubMed1990

Evidence for substrate channeling in the early steps of cholesterogenesis.

We have directly tested the ability of acetoacetate, upon activation to the CoA thioester, to channel into the cholesterogenic pathway prior to scrambling of its carbon skeleton with the acetate pool. The approach relies upon trapping [3-13C]acetoacetate-derived hydroxymethylglutaryl-CoA, hydrolyzing this metabolite, and esterifying the resulting hydroxymethylglutaric acid to allow gas chromatography/mass spectrometry analysis of the dimethyl esters for the 13C enrichment and labeling pattern. 99% enriched [3-13C] and [1,3,5-13C]hydroxymethylglutaric acid samples were synthesized, providing standards against which physiological samples could be compared. Cytosolic extracts from brain and liver of cholestyramine-fed rats were incubated with [3-13C]acetoacetate (2 mM) or with [1-13C]acetate (5 mM). In contrast to [13C]acetate-derived hydroxymethylglutarate, which shows the expected triple labeling pattern, [13C]acetoacetate-derived hydroxymethylglutarate from both liver and brain extracts is predominantly monolabeled. These data suggest that, after acetoacetate is activated to the CoA thioester, cytosolic hydroxymethylglutaryl-CoA synthase effectively commits much of this acetoacetyl-CoA to cholesterogenesis before thiolase can scramble the carbon skeleton of the acetoacetyl moiety into the acetate pool. This chemical approach represents an alternative method for testing the channeling of metabolites through sequential steps in a metabolic pathway. Such a method may be useful when physical or kinetic techniques prove to be unsuitable.

Acetates↗
PubMed1983

Ketone body, glucose, lactic acid, and amino acid utilization by tumors in vivo in fasted rats.

Arteriovenous differences for acetoacetate, beta-hydroxybutyrate, glucose, lactic acid, and glutamine and other amino acids were measured across Morris hepatomas 5123C, 7777, and 7288CTCF and Walker sarcocarcinoma 256 in vivo in rats fasted for 2 days. The acetoacetate and beta-hydroxybutyrate concentrations in arterial whole blood of fasted tumor-bearing rats were 0.52 +/- 0.06 and 1.82 +/- 0.19 mM (S.E., n = 38), respectively. Both ketone bodies were utilized by the tumors, and the rates of utilization were directly related to the rates of supply. The mean utilization rates for acetoacetate and beta-hydroxybutyrate were 13.9 +/- 2.9 (range, 0 to 64; n = 30) and 24.7 +/- 4.4 (range, 0 to 145; n = 38) nmol/min/g tumor wet weight, respectively. Eight of the tumors produced acetoacetate, presumably from utilized beta-hydroxybutyrate. An average of 52% of the acetoacetate and 30% of the beta-hydroxybutyrate carried in the arterial blood was removed during one pass through the tumors. The concentrations of glucose and glutamine in the arterial whole blood of fasted tumor-bearing rats (n = 38) were 6.55 +/- 0.3 and 0.76 +/- 0.02 mM, respectively; both of these substrates were utilized at rates that were directly proportional to the rates of supply. The mean rates of glucose and glutamine utilization for all tumors in fasted rats were 101 +/- 11 (range, 3 to 313) and 8.2 +/- 1.1 (range, 0 to 25.1) nmol/min/g tumor wet weight, respectively. Thirty-six % of the glucose and 25% of the glutamine supplied to the tumors was utilized. Comparison (by linear regression and analysis of covariance) of the rates of supply and utilization of glucose and glutamine in tumors growing in fasted versus fed rats indicated that these substrates are utilized more efficiently by tumors growing in fasted animals. Lactic acid was either produced or utilized, depending on the arterial whole-blood concentration. Production or utilization occurred, respectively, when the arterial lactate concentration was less or greater than 1 to 3 mM. The arterial whole-blood amino acids (except glutamine) were utilized at rates that ranged from 1 to 4 nmol/min/g tumor wet weight. The results indicate that energy production for tumor growth in fasted rats is supported, in part, by an increased availability of ketone bodies, by an increased efficiency of utilization of glucose and glutamine, and, under certain circumstances, by utilization of lactic acid.

3-Hydroxybutyric Acid↗
PubMed1980

Dissociation between mitochondria calcium ion release and pyridine nucleotide oxidation.

In the presence of phosphate, both acetoacetate and palmitoyl-coenzyme A induce pyridine nucleotide oxidation, swelling of mitochondria, and Ca2+ release. However, when mitochondria accumulate Ca2+ in the presence of lactate, neither acetoacetate nor palmitoyl-CoA addition results in Ca2+ release and no swelling is observed. If ruthenium red is added prior to these releasing agents, a 10-fold greater rate of Ca2+ efflux is observed when phosphate is present compared to lactate alone. Although acetoacetate produces significant oxidation of NADH in the lactate-supplemented medium, no Ca2+ release occurs. In the lactate medium, no oxidation of pyridine nucleotide was seen following palmitoyl-CoA addition. Lactate-supported Ca2+ accumulation (+/- N-ethylmaleimide) produces a transient respiratory stimulation associated with active Ca2+ uptake. Addition of phosphate to Ca2+-loaded mitochondria (lactate medium) promotes respiratory stimulation and Ca2+ efflux upon addition of acetoacetate or palmitoyl-CoA. When N-ethylmaleimide is present to inhibit the phosphate-hydroxyl exchange, no efflux of Ca2+ occurs after addition of phosphate and acetoacetate or phosphate and palmitoyl-CoA. The ionophore, A23187, produces Ca2+ release from mitochondria in either lactate (+/- N-ethylmaleimide) or phosphate medium. These results suggest that activation by the reduction state of mitochondrial pyridine nucleotides but may also depend upon the nature of the accompanying anion, as well as membrane permeability alterations.

Acetoacetates↗
PubMed1978

Modification of the alkaline picrate assay for creatinine to prevent spuriously elevated values by keto acids.

Acetoacetate and pyruvate, sometimes present in patients' serum in abnormal amounts, interfere, like other keto acids, with the determination by some usual procedures of creatinine. Acetoacetate can be responsible for overestimation of "creatinine" in the order of 400 mumol/l in sera of ketotic diabetics, fasting subjects and other patients with ketosis. The pseudocreatinine reaction of acetoacetate increases with increasing concentration of NaOH and picrate. Pyruvate causes falsely elevated values, especially at high picrate concentrations. The effect of acetoacetate at 25 degrees C has ceased 90 sec after the start of the reaction. We propose a continuous flow method with relatively low concentrations of NaOH and picrate, and a kinetic method at 25 degrees C with a measuring time of between 90 and 270 sec after mixing sample and reagents. In this way the interference by acetoacetate and pyruvate is eliminated or reduced. We found excellent correlation between the proposed method for a centrifugal analyzer and a manual reference method, based on the adsorption of creatinine to fuller's earth.

Creatinine↗
PubMed1980

A possible mechanism for the anti-ketogenic action of alanine in the rat.

1. The anti-ketogenic effect of alanine has been studied in normal starved and diabetic rats by infusing l-alanine for 90min in the presence of somatostatin (10mug/kg body wt. per h) to suppress endogenous insulin and glucagon secretion. 2. Infusion of alanine at 3mmol/kg body wt. per h caused a 70+/-11% decrease in [3-hydroxybutyrate] and a 58+/-9% decrease in [acetoacetate] in 48h-starved rats. [Glucose] and [lactate] increased, but [non-esterified fatty acid], [glycerol] and [3-hydroxybutyrate]/[acetoacetate] were unchanged. 3. Infusion of alanine at 1mmol/kg body wt. per h caused similar decreases in [ketone body] (3-hydroxybutyrate plus acetoacetate) in 24h-starved normal and diabetic rats, but no change in other blood metabolites. 4. Alanine [3mmol/kg body wt. per h] caused a 72+/-9% decrease in the rate of production of ketone bodies and a 57+/-8% decrease in disappearance rate as assessed by [3-(14)C]acetoacetate infusion. Metabolic clearance was unchanged, indicating that the primary effect of alanine was inhibition of hepatic ketogenesis. 5. Aspartate infusion at 6mmol/kg body wt. per h had similar effects on blood ketone-body concentrations in 48h-starved rats. 6. Alanine (3mmol/kg body wt. per h) caused marked increases in hepatic glutamate, aspartate, malate, lactate and citrate, phosphoenolpyruvate, 2-phosphoglycerate and glucose concentrations and highly significant decreases in [3-hydroxybutyrate] and [acetoacetate]. Calculated [oxaloacetate] was increased 75%. 7. Similar changes in hepatic [malate], [aspartate] and [ketone bodies] were found after infusion of 6mmol of aspartate/kg body wt. per h. 8. It is suggested that the anti-ketogenic effect of alanine is secondary to an increase in hepatic oxaloacetate and hence citrate formation with decreased availability of acetyl-CoA for ketogenesis. The reciprocal negative-feedback cycle of alanine and ketone bodies forms an important non-hormonal regulatory system.

Alanine↗
PubMed1999

Non-specific immunity and ketone bodies. I: In vitro studies on chemotaxis and phagocytosis in ovine neutrophils.

The in vitro effects of the ketone bodies beta-OH-butyrate (2.4 or 4.8 mmol/l) and acetoacetate (2.4 or 4.8 mmol/l) on the uptake of latex particles (1.09 microns) and chemotaxis were investigated in ovine neutrophils. Because the acetoacetate used was a lithium salt, the effect of 2.4 or 4.8 mmol/l lithium chloride was also tested. Neutrophils from eight non-lactating, non-pregnant ewes were studied. The uptake of latex particles, as measured by a spectrophotometric method, showed wide individual variation. The phagocytotic activity was unaffected by 2.4 mmol/l ketone bodies and LiCl, but it was significantly inhibited by 4.8 mmol/l beta-OH-butyrate and activated by 4.8 mmol/l LiCl. The latter result could be masking an inhibitory effect of acetoacetate. Chemotactic movements of neutrophils, as evaluated in a modified Boyden chamber using homologous zymosan-activated serum (ZAS) as a chemoattractant, were slightly but significantly reduced by a 2.4 mmolar concentration of the ketone bodies, administered singly or simultaneously, and by LiCl. We conclude therefore that the inhibitory effect of lithium-acetoacetate could be due to its lithium component. The 4.8 mmol/l dose of acetoacetate and beta-OH butyrate significantly decreased chemotaxis only when both compounds were added simultaneously. No effect of 4.8 mmol/l LiCl was observed. These results suggest that ketone bodies, in particular beta-OH butyrate, could directly influence particle uptake and chemotaxis in neutrophils. Although other factors could decrease the efficiency of the immune system in ketotic ruminants, the effects of the ketone bodies on neutrophils functions may explain the high frequency of infectious disease during 'ketotic syndrome'. The immunomodulatory effect of lithium needs to be evaluated further and it should be considered when testing lithium compounds.

Animals↗
PubMed1982

Utilization of nutrients by isolated epithelial cells of the rat colon.

Isolated suspensions of colonocytes from the rat were used to assess utilization, interaction, and fate of metabolic substrates normally obtained from colonic bacteria (acetate, propionate, butyrate) or derived from the blood circulation to the colonic mucosa (D-glucose, acetoacetate, L-glutamine). The short-chain fatty acid n-butyrate (10 mM), on its own, accounted for 86% of the total oxygen consumption and suppressed oxidation of endogenous fuel by 82%. Ths value was not altered by the addition of acetoacetate (5 mM), of L-glutamine (5 mM), or of D-glucose (10 mM). Activation of short-chain fatty acids by colonocytes proceeded in the order of butyrate greater than acetate greater than propionate. D-Glucose on its own accounted for 30% of the oxygen consumption by colonocytes and hardly suppressed utilization of endogenous fuels. Colonocytes utilized ketone bodies (acetoacetate) and produced them (acetoacetate and beta-hydroxybutyrate) from short-chain fatty acids. Considering the interaction of substrates, isolated colonic epithelial cells utilized respiratory fuels in the preferential order of butyrate greater than acetoacetate greater than glutamine greater than glucose. The high rate of CO2 production from butyrate should be a worthwhile means of examining the functional activity of the colonic mucosa clinically and in vivo.

Ammonia↗
PubMed1982

Utilization of ketone bodies and glucose by established neural cell lines.

The rates of utilization of [3-14C]-acetoacetate, [3-14C]-3-hydroxybutyrate, and [6-14C]-glucose were measured in four established cell lines from neuroblastoma of rat (B103) and mouse (N4TG1) and from rat astrocytoma (RGC6) and mouse oligodendroglia (G2620). The rates of incorporation of acetoacetate into lipid were 3-5 times higher than glucose in all cell lines. The incorporation of 3-hydroxybutyrate was similar to that of glucose. Thin-layer chromatography of the total lipid extracts showed the same relative rates of use of these substrates for synthesis of various phospholipids and neutral lipids. The rates of incorporation into neutral lipids and phosphatidylcholine were essentially linear for 12 hr; however, that into phosphatidylethanolamine was markedly higher in the second 6 hr interval than in the first. In all cases, the greatest percentage of label (35-50%) appeared in the phosphatidylcholine fraction. The distribution of label from each of the three substrates among the various lipids was similar in the glial cells, but there were marked differences in distribution of the two ketone bodies in the neuroblastoma lines. These cells also synthesized lipids that migrated to the same area on the chromatogram as cholesterol esters and free fatty acids. In three of the four cell lines the rates of oxidation were highest for glucose, intermediate for acetoacetate, and lowest for 3-hydroxybutyrate. The ratios of the rate of incorporation to the rate of oxidation were higher for ketone bodies (3.32 for 3-hydroxybutyrate and 5.29 for acetoacetate) than for glucose (0.41). This indicates that in these cells ketone bodies are directed toward lipid synthesis rather than oxidation, and glucose is preferentially used as an energy source.

3-Hydroxybutyric Acid↗
PubMed1988

Effect of insulin on ketone body clearance studied by a ketone body "clamp" technique in normal man.

The effect of elevated plasma insulin concentration (55 +/- 2 mU/l) on peripheral clearance and production of total ketone bodies was determined using 3-14C-acetoacetate tracer infusions. Nine normal subjects were studied twice, once during insulin infusion (20 mU.m-2.min-1), once during basal plasma insulin concentrations (controls). Blood total ketone body concentrations (sum of acetone, acetoacetate and beta-hydroxybutyrate) were maintained in both studies at 2 mmol/l by feedback-controlled sodium acetoacetate infusions. The coefficient of variation of total ketone body concentrations during the two clamp studies was 10 and 11% respectively. The sodium acetoacetate infusion rate required during the clamp was 55 +/- 4% higher during hyperinsulinaemia than in controls (p less than 0.005). This was due to increased total ketone body clearance (8.4 +/- 0.7 vs 6.7 +/- 0.4 ml.kg-1.min-1, p less than 0.015), and to enhanced suppression of ketone body production (p less than 0.01). Hyperketonaemia alone decreased ketone body production by 42% and diminished ketone body clearance by 46%, the former being enhanced, the latter being in part antagonised by insulin. Since the plasma insulin concentrations were within those observed in patients treated for diabetic ketoacidosis, the data suggest that the antiketotic effect of insulin therapy results in part from an increase in peripheral ketone body disposal.

Acetoacetates↗