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PubMed1982

Effects of adrenaline on ketogenesis from long- and medium-chain fatty acids in starved rats.

1. Injection of adrenaline into 24 h-starved rats caused a 69% decrease in blood [ketone-body] (3-hydroxybutyrate plus acetoacetate), accompanied by a decreased [3-hydroxybutyrate]/[acetoacetate] ratio. Blood [glucose] and [lactate] increased, but [alanine] was unchanged. 2. Adrenaline also decreased [ketone-body] after intragastric feeding of both long- and medium-chain triacylglycerol. The latter decrease was observed after suppression of lipolysis with 5-methylpyrazole-3-carboxylic acid, indicating that the antiketogenic action of adrenaline was not dependent on the chain length of the precursor fatty acid. 3. The actions of adrenaline to decrease blood [ketone-body] and to increase blood [glucose] were not observed after administration of 3-mercaptopicolinate, an inhibitor of gluconeogenesis. This suggests that these effects of the hormone are related. 4. The possible clinical significance of the results is discussed with reference to the restricted ketosis often observed after surgical or orthopaedic injury.

Animals↗

PubMed1986

Ketone-body metabolism in tumour-bearing rats.

During starvation for 72 h, tumour-bearing rats showed accelerated ketonaemia and marked ketonuria. Total blood [ketone bodies] were 8.53 mM and 3.34 mM in tumour-bearing and control (non-tumour-bearing) rats respectively (P less than 0.001). The [3-hydroxybutyrate]/[acetoacetate] ratio was 1.3 in the tumour-bearing rats, compared with 3.2 in the controls at 72 h (P less than 0.001). Blood [glucose] and hepatic [glycogen] were lower at the start of starvation in tumour-bearing rats, whereas plasma [non-esterified fatty acids] were not increased above those in the control rats during starvation. After functional hepatectomy, blood [acetoacetate], but not [3-hydroxybutyrate], decreased rapidly in tumour-bearing rats, whereas both ketone bodies decreased, and at a slower rate, in the control rats. Blood [glucose] decreased more rapidly in the hepatectomized control rats. Hepatocytes prepared from 72 h-starved tumour-bearing and control rats showed similar rates of ketogenesis from palmitate, and the distribution of [1-14C] palmitate between oxidation (ketone bodies and CO2) and esterification was also unaffected by tumour-bearing, as was the rate of gluconeogenesis from lactate. The carcinoma itself showed rapid rates of glycolysis and a poor ability to metabolize ketone bodies in vitro. The results are consistent with the peripheral, normal, tissues in tumour-bearing rats having increased ketone-body and decreased glucose metabolic turnover rates.

Animals↗

PubMed1986

Metabolism of glucose, glutamine, long-chain fatty acids and ketone bodies by murine macrophages.

Maximum activities of some key enzymes of metabolism were studied in elicited (inflammatory) macrophages of the mouse and lymph-node lymphocytes of the rat. The activity of hexokinase in the macrophage is very high, as high as that in any other major tissue of the body, and higher than that of phosphorylase or 6-phosphofructokinase, suggesting that glucose is a more important fuel than glycogen and that the pentose phosphate pathway is also important in these cells. The latter suggestion is supported by the high activities of both glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase. However, the rate of glucose utilization by 'resting' macrophages incubated in vitro is less than the 10% of the activity of 6-phosphofructokinase: this suggests that the rate of glycolysis is increased dramatically during phagocytosis or increased secretory activity. The macrophages possess higher activities of citrate synthase and oxoglutarate dehydrogenase than do lymphocytes, suggesting that the tricarboxylic acid cycle may be important in energy generation in these cells. The activity of 3-oxoacid CoA-transferase is higher in the macrophage, but that of 3-hydroxybutyrate dehydrogenase is very much lower than those in the lymphocytes. The activity of carnitine palmitoyltransferase is higher in macrophages, suggesting that fatty acids as well as acetoacetate could provide acetyl-CoA as substrate for the tricarboxylic acid cycle. No detectable rate of acetoacetate or 3-hydroxybutyrate utilization was observed during incubation of resting macrophages, but that of oleate was 1.0 nmol/h per mg of protein or about 2.2% of the activity of palmitoyltransferase. The activity of glutaminase is about 4-fold higher in macrophages than in lymphocytes, which suggests that the rate of glutamine utilization could be very high. The rate of utilization of glutamine by resting incubated macrophages was similar to that reported for rat lymphocytes, but was considerably lower than the activity of glutaminase.

Animals↗

PubMed1992

Platelet-activating factor causes hypoketonaemia in starved rats.

1. The aim of this work was to examine whether platelet-activating factor could mimic the hypoketonaemia seen in septic and endotoxic experimental animals. Platelet-activating factor was administered either by the intraperitoneal (high dose) or intravenous (jugular vein, low dose) routes. 2. Intraperitoneal injection of platelet-activating factor (25 micrograms/kg body weight) decreased the blood ketone body concentration (acetoacetate plus 3-hydroxybutyrate) transiently (30 min after injection) in starved rats. Continuous intravenous infusion of platelet-activating factor (40 ng min-1 kg-1 for 5 h) caused comparable hypoketonaemia. 3. The hepatic acetoacetate concentration also decreased transiently after injection of platelet-activating factor and there was an increase in the 3-hydroxybutyrate/acetoacetate ratio. The hepatic ATP concentration decreased at 15 and 30 min after injection of platelet-activating factor. Infusion of platelet-activating factor caused a similar decrease in hepatic ketone body concentration, but no significant change in the 3-hydroxybutyrate/acetoacetate ratio or adenine nucleotide concentrations. 4. Platelet-activating factor administered by infusion, but not by injection, decreased the plasma non-esterified fatty acid concentration. The plasma glycerol concentration also decreased after infusion of platelet-activating factor, suggesting decreased lipolysis in adipose tissue. 5. Changes in plasma insulin concentration or white adipose tissue blood flow did not appear to contribute to the decrease in the plasma non-esterified fatty acid concentration after infusion of platelet-activating factor. However, there was a significant decrease in blood flow to interscapular brown adipose tissue in both the infused and injected groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗

PubMed1993

Sulphide impairment of substrate oxidation in rat colonocytes: a biochemical basis for ulcerative colitis?

1. Isolated colonic epithelial cells of the rat were incubated for 40 min with [6-14C]glucose and n-[1-14C]butyrate in the presence of 0.1-2.0 mmol/l NaHS, a concentration range found in the human colon. Metabolic products, 14CO2, acetoacetate, beta-hydroxybutyrate and lactate, were measured and injury to cells was judged by diminished production of metabolites. 2. Oxidation of n-butyrate to CO2 and acetoacetate was reduced at 0.1 and 0.5 mmol/l NaHS, whereas glucose oxidation remained unimpaired. At 1.0-2.0 mmol/l NaHS, n-butyrate and glucose oxidation were dose-dependently reduced at the same rate. 3. To bypass short-chain acyl-CoA dehydrogenase activity necessary for butyrate oxidation, ketogenesis from crotonate was measured in the presence of 1.0 mmol/l NaHS. Suppression by sulphide of ketogenesis from crotonate (-10.5 +/- 6.1%) compared with control conditions was not significant, whereas suppression of ketogenesis from n-butyrate (-36.00 +/- 5.14%) was significant (P = < 0.01). Inhibition of FAD-linked oxidation was more affected by NaHS than was NAD-linked oxidation. 4. L-Methionine (5.0 mmol/l) significantly redressed the impaired beta-oxidation induced by NaHS. Methionine equally improved CO2 and ketone body production, suggesting a global reversal of the action of sulphide. 5. Sulphide-induced oxidative changes closely mirror the impairment of beta-oxidation observed in colonocytes of patients with ulcerative colitis. A hypothesis for the disease process of ulcerative colitis is that sulphides may form persulphides with butyryl-CoA, which would inhibit cellular short-chain acyl-CoA deHydrogenase and beta-oxidation to induce an energy-deficiency state in colonocytes and mucosal inflammation.

Animals↗

PubMed2004

Bacterial acetone carboxylase is a manganese-dependent metalloenzyme.

Bacterial acetone carboxylase catalyzes the ATP-dependent carboxylation of acetone to acetoacetate with the concomitant production of AMP and two inorganic phosphates. The importance of manganese in Rhodobacter capsulatus acetone carboxylase has been established through a combination of physiological, biochemical, and spectroscopic studies. Depletion of manganese from the R. capsulatus growth medium resulted in inhibition of acetone-dependent but not malate-dependent cell growth. Under normal growth conditions (0.5 microm Mn2+ in medium), growth with acetone as the carbon source resulted in a 4-fold increase in intracellular protein-bound manganese over malate-grown cells and the appearance of a Mn2+ EPR signal centered at g = 2 that was absent in malate-grown cells. Acetone carboxylase purified from cells grown with 50 microm Mn2+ had a 1.6-fold higher specific activity and 1.9-fold higher manganese content than cells grown with 0.5 microm Mn2+, consistently yielding a stoichiometry of 1.9 manganese/alpha2beta2gamma2 multimer, or 0.95 manganese/alphabetagamma protomer. Manganese in acetone carboxylase was tightly bound and not removed upon dialysis against various metal ion chelators. The addition of acetone to malate-grown cells grown in medium depleted of manganese resulted in the high level synthesis of acetone carboxylase (15-20% soluble protein), which, upon purification, exhibited 7% of the activity and 6% of the manganese content of the enzyme purified from acetone-grown cells. EPR analysis of purified acetone carboxylase indicates the presence of a mononuclear Mn2+ center, with possible spin coupling of two mononuclear sites. The addition of Mg.ATP or Mg.AMP resulted in EPR spectral changes, whereas the addition of acetone, CO2, inorganic phosphate, and acetoacetate did not perturb the EPR. These studies demonstrate that manganese is essential for acetone carboxylation and suggest a role for manganese in nucleotide binding and activation.

Acetone↗

PubMed2005

Ketone bodies stimulate chaperone-mediated autophagy.

Chaperone-mediated autophagy (CMA) is a selective lysosomal protein degradative process that is activated in higher organisms under conditions of prolonged starvation and in cell culture by the removal of serum. Ketone bodies are comprised of three compounds (beta-hydroxybutyrate, acetoacetate, and acetone) that circulate during starvation, especially during prolonged starvation. Here we have investigated the hypothesis that ketone bodies induce CMA. We found that physiological concentrations of beta-hydroxybutyrate (BOH) induced proteolysis in cells maintained in media with serum and without serum; however, acetoacetate only induced proteolysis in cells maintained in media with serum. Lysosomes isolated from BOH-treated cells displayed an increased ability to degrade both glyceraldehyde-3-phosphate dehydrogenase and ribonuclease A, substrates for CMA. Isolated lysosomes from cells maintained in media without serum also demonstrated an increased ability to degrade glyceraldehyde-3-phosphate dehydrogenase and ribonuclease A when the reaction was supplemented with BOH. Such treatment did not affect the levels of lysosome-associated membrane protein 2a or lysosomal heat shock cognate protein of 70 kDa, two rate-limiting proteins in CMA. However, pretreatment of glyceraldehyde-3-phosphate and ribonuclease A with BOH increased their rate of degradation by isolated lysosomes. Lysosomes pretreated with BOH showed no increase in proteolysis, suggesting that BOH acts on the substrates to increase their rates of proteolysis. Using OxyBlot analysis to detect carbonyl formation on proteins, one common marker of protein oxidation, we showed that treatment of substrates with BOH increased their oxidation. Neither glycerol, another compound that increases in circulation during prolonged starvation, nor butanol or butanone, compounds closely related to BOH, had an effect on CMA. The induction of CMA by ketone bodies may provide an important physiological mechanism for the activation of CMA during prolonged starvation.

Antigens, CD↗

PubMed2006

Agmatine stimulates hepatic fatty acid oxidation: a possible mechanism for up-regulation of ureagenesis.

We demonstrated previously in a liver perfusion system that agmatine increases oxygen consumption as well as the synthesis of N-acetylglutamate and urea by an undefined mechanism. In this study our aim was to identify the mechanism(s) by which agmatine up-regulates ureagenesis. We hypothesized that increased oxygen consumption and N-acetylglutamate and urea synthesis are coupled to agmatine-induced stimulation of mitochondrial fatty acid oxidation. We used 13C-labeled fatty acid as a tracer in either a liver perfusion system or isolated mitochondria to monitor fatty acid oxidation and the incorporation of 13C-labeled acetyl-CoA into ketone bodies, tricarboxylic acid cycle intermediates, amino acids, and N-acetylglutamate. With [U-13C16] palmitate in the perfusate, agmatine significantly increased the output of 13C-labeled beta-hydroxybutyrate, acetoacetate, and CO2, indicating stimulated fatty acid oxidation. The stimulation of [U-13C16]palmitate oxidation was accompanied by greater production of urea and a higher 13C enrichment in glutamate, N-acetylglutamate, and aspartate. These observations suggest that agmatine leads to increased incorporation and flux of 13C-labeled acetyl-CoA in the tricarboxylic acid cycle and to increased utilization of 13C-labeled acetyl-CoA for synthesis of N-acetylglutamate. Experiments with isolated mitochondria and 13C-labeled octanoic acid also demonstrated that agmatine increased synthesis of 13C-labeled beta-hydroxybutyrate, acetoacetate, and N-acetylglutamate. The current data document that agmatine stimulates mitochondrial beta-oxidation and suggest a coupling between the stimulation of hepatic beta-oxidation and up-regulation of ureagenesis. This action of agmatine may be mediated via a second messenger such as cAMP, and the effects on ureagenesis and fatty acid oxidation may occur simultaneously and/or independently.

Adenosine Diphosphate↗

PubMed1981

The metabolic response to yellow fever immunization: protein-sparing modified fast.

The metabolic response to yellow fever immunization was investigated in five obese patients who were consuming a protein-sparing modified fast for 3 wk. Fasting 1/2, 1, and 2 h postprandial values for insulin, glucagon, glucose, lactate, beta hydroxybutyrate, acetoacetate, and free fatty acids were assessed before and the 1st, 3rd, and 5th day after immunization. The hormone and substrate responses to meat ingestion in patients well adapted to a protein-sparing modified fast and prior to infection was a rise in glucagon, no change in insulin, lactate, or ketone bodies and slight increase in serum free fatty acid and glucose levels. Over the entire period a significant (p less than 0.01) postprandial rise in glucagon was noted. Significant increases in insulin (p less than 0.01) and lactate (p less than 0.01) and falls in beta hydroxybutyrate (p less than 0.01) and acetoacetate (p less than 0.01) were noted in the postinfection period. There was also a significant interaction of diet and infection to increase insulin levels (p less than 0.05). The clinically mild infection produced by yellow fever immunization elicits a metabolic response which thus may be useful to investigate intermediary metabolism in the hospital setting.

Adult↗

PubMed1976

Blood metabolites and glucose metabolism in the fed and fasted chicken.

The effect of fasting on blood metabolites and glucose metabolism in the chicken was studied. Parameters of glucose metabolism were estimated in vivo using a single injection of [2-3H]-glucose or [6-3H]-glucose in combination with [U-14C]-glucose. Plasma glucose, blood lactate and blood acetoacetate levels were not significantly changed in chickens fasted for 72 hours. Pyruvate levels in chickens fasted for 24 hours were higher than those observed in blood from birds fasted 0 to 72 hours. Further, the lactate to pyruvate ratio was lower in chickens fasted for 24 to 72 hours than in fed chickens. Fasting chickens for 24 or 72 hours resulted in three- to fivefold increase in blood beta-hydroxybutyrate levels and a significant increase in beta-hydroxybutyrate to acetoacetate ratio. Plasma levels of alanine and serine were increased after a 24 hour fast but were not further changed when fasting was extended to 72 hours. Plasma aspartate and glutamate levels were not significantly changed in chickens fasted for 24 hours but were markedly decreased in chickens fasted for 72 hours. Plasma levels of glycine were significantly lower in chickens fasted 24 or 72 hours than in fed birds. Glucose replacement rates estimated with [2-3H]-glucose in chickens fasted 0,24 and 72 hours were 14.3, 9.1 and 9.4 mg glucose/minute/kg body weight, respectively. Fasting up to 72 hours did not influence the total body glucose mass in the chickens. The degree of glucose-carbon recycling in 24-hour fasted chickens estimated by using [2-3H]- and [U-14C]-glucose or [6-3H]- and [U-14C]-glucose averaged 42% to 52% and 27% to 30%, respectively. These observations indicate that rate of glucose utilization in the chicken is rapid and that substantial recycling of glucose carbon occurs in fasted chickens.

Amino Acids↗

PubMed1978

The effects of fasting on body composition, glucose turnover, enzymes and metabolites in the chicken.

Chickens (1,200 g) were fasted 1, 4, or 8 days. Significant decreases occurred in total body protein and fat with fasting, with the greatest energy loss from fat. Glucose production determined with either [2-3H] or [6-3H] glucose injected simultaneously with [U-14C] glucose remained constant with fasting at 10 to 13 mg/minute/kg body weight which is much higher than reported for mammals. Blood lactate and glycerol were unchanged with fasting, while pyruvate increased and plateaued. Plasma alanine, serine and glycine levels were extremely high compared to values in fasted mammals. Blood beta-hydroxybutyrate increased dramatically with fasting (350 to 3,500 nm/ml), while acetoacetate remained constant. The hepatic lactate: pyruvate ratio was unchanged with fasting, while the beta-hydroxybutyrate:acetoacetate ratio increased. These ratios have been reported to influence phosphoenolpyruvate (PEP) and glucose production in mammals. Hepatic and renal phospyoenolpyruvate carboxykinase (PEPCK) levels remained constant, while hepatic lactate dehydrogenase increased with fasting. Beta-Hydroxybutyrate dehydrogenase levels were very low at all times. The results indicate little glucose sparing adaptation per kg in the fasting chicken.

Animals↗

PubMed1991

Evaluation of energy sources with and without carnitine in newborn pig heart and liver.

The oxidation rate of five energy substrates with and without exogenous addition of carnitine in the heart and liver of 15-h-old nonsuckled piglets was evaluated. Oxygen consumption (nmol O2.mg protein-1.min-1) in heart and liver for five substrates were: pyruvate, 0.248, 0.191; palmitoyl-CoA, 0.042, 0.034; palmitoyl-carnitine, 0.249, 0.111; isovalerate, 0.084, 0.059; acetoacetate, 0.166, 0.068, respectively. The addition of free carnitine doubled the rate of palmitoyl-CoA utilization in both heart and liver, but palmitoyl-CoA oxidation was always much lower than that of palmitoyl-carnitine. In livers of piglets from sows fed 8% fat, palmitoyl-carnitine oxidation was slower (P less than 0.03) than in piglets from sows fed 0% fat. Heart tissue metabolized isovalerate faster (P less than 0.02) when piglets were from sows fed fat compared with those from the nonfat group. A lysine x fat interaction was observed for piglet liver metabolism of isovalerate and acetoacetate, suggesting that a more metabolically developed pig results when sows are fed 0.48% lysine without supplemental fat during gestation. Carnitine did not seem to be the limiting factor for the oxidation of palmitoyl-CoA, and gestational dietary fat and lysine seemed to influence substrate metabolism in the newborn pig.

Animals↗

PubMed1996

Isolation and characterization of a new gram-negative, acetone-degrading, nitrate-reducing bacterium from soil, Paracoccus solventivorans sp. nov.

An acetone-degrading, nitrate-reducing, coccoid to rod-shaped bacterium, strain L1, was isolated from soil on the site of a natural gas company. Cells of the logarithmic growth phase reacted gram positive, while those of the stationary growth phase were gram negative. Single organisms were 0.4 to 0.5 by 0.9 to 1.5 microns in size, nonmotile, and non-spore forming and had poly-beta-hydroxybutyrate inclusions. The doubling time of strain L1 on acetone-CO2-nitrate at the optimal pH of 7 to 8 and the optimal temperature of 30 to 37 degrees C was 12 h. More than 0.2% NaCl or 10 mM thiosulfate inhibited growth. For oxygen or nitrate respiration, acetone and a few organic chemicals were utilized as carbon sources whereas many others could not be used (for details, see Results). Bicarbonate (or CO2) was essential for growth on acetone but not for growth on acetoacetate. The growth yields for acetone-CO2 and acetoacetate were 28.3 and 27.3 g/mol, respectively. With acetone as the carbon source, poly-beta-hydroxybutyrate accounted for up to 40% of the cellular dry weight. The DNA of strain L1 had a G + C content of 68.5 mol% (as determined by high-performance liquid chromatography of nucleotides) or 70 mol% (as determined by the TM method). The sequence of the gene coding for the 16S rRNA led to the classification of strain L1 in the paracoccus group of the alpha subclass of the Proteobacteria. The new isolate is named Paracoccus solventivorans sp. nov. DSM 6637.

Acetone↗

PubMed2001

Crystallization and preliminary X-ray analysis of a NADPH 2-ketopropyl-coenzyme M oxidoreductase/carboxylase.

NADPH 2-ketopropyl-coenzyme M (2-mercaptoethanesulfonate) oxidoreductase/carboxylase is the terminal enzyme in a metabolic pathway that results in the conversion of propylene to the central metabolite acetoacetate. This enzyme is an FAD-containing enzyme that is a member of the NADPH:disulfide oxidoreductase family of enzymes and catalyzes the cleavage and carboxylation of 2-ketopropyl-coenzyme M to form acetoacetate and coenzyme M. Crystallization trials have revealed that the highest diffraction quality crystals (better that 2.0 A resolution) could be achieved when the substrate or product of the reaction was added to the enzyme in a stoichiometric excess.

Crystallization↗

PubMed2004

Structure of the CoA transferase from pig heart to 1.7 A resolution.

Succinyl-CoA:3-ketoacid CoA transferase (SCOT; EC 2.8.3.5) activates the acetoacetate in ketone bodies by transferring the CoA group from succinyl-CoA to acetoacetate to produce acetoacetyl-CoA and succinate. In the reaction, a glutamate residue at the active site of the enzyme forms a thioester bond with CoA and in this form the enzyme is subject to autolytic fragmentation. The crystal structure of pig heart SCOT has been solved and refined to 1.7 A resolution in a new crystal form. The structure shows the active-site glutamate residue in a conformation poised for autolytic fragmentation, with its side chain accepting one hydrogen bond from Asn281 and another from its own amide N atom. However, the conformation of this glutamate side chain would have to change for the residues that are conserved in the CoA transferases (Gln99, Gly386 and Ala387) to participate in stabilizing the tetrahedral transition states of the catalytic mechanism. The structures of a deletion mutant in two different crystal forms were also solved.

Amino Acid Sequence↗

PubMed1998

Comparative analysis of blood chemical values in primary ketosis and abomasal displacement in cows.

Blood chemical values, including ketone bodies, were measured in 25 cows with abomasal displacement (displacement group), 16 cows with primary ketosis (ketosis group), and nine normal controls to investigate the pathophysiology of abomasal displacement. Increases in aspartate aminotransferase, gamma-glutamyl transpeptidase, non-esterified fatty acid (NEFA), and ketone bodies (3-hydroxybutyric acid and acetoacetic acid) were observed in the displacement and ketosis groups. Total cholesterol increased significantly in the ketosis group but decreased in the displacement group. Glucose was significantly low and reversely correlated to ketone bodies in the ketosis group but was not low and was not correlated with ketone bodies in the displacement group. While NEFA was correlated to ketone bodies in the ketosis group, it was not in the displacement group. A correlation between the values of acetoacetic acid and 3-hydroxybutyric acid was seen in both the ketosis and displacement groups. The fact that blood chemical values in ketosis cows were clearly different from those in displacement cows suggest that the biochemical mechanism of ketogenesis is different between these two groups.

Abomasum↗

PubMed2006

Identity of SMCT1 (SLC5A8) as a neuron-specific Na+-coupled transporter for active uptake of L-lactate and ketone bodies in the brain.

SMCT1 is a sodium-coupled (Na(+)-coupled) transporter for l-lactate and short-chain fatty acids. Here, we show that the ketone bodies, beta-d-hydroxybutyrate and acetoacetate, and the branched-chain ketoacid, alpha-ketoisocaproate, are also substrates for the transporter. The transport of these compounds via human SMCT1 is Na(+)-coupled and electrogenic. The Michaelis constant is 1.4 +/- 0.1 mm for beta-d-hydroxybutyrate, 0.21 +/- 0.04 mm for acetoacetate and 0.21 +/- 0.03 mm for alpha-ketoisocaproate. The Na(+) : substrate stoichiometry is 2 : 1. As l-lactate and ketone bodies constitute primary energy substrates for neurons, we investigated the expression pattern of this transporter in the brain. In situ hybridization studies demonstrate widespread expression of SMCT1 mRNA in mouse brain. Immunofluorescence analysis shows that SMCT1 protein is expressed exclusively in neurons. SMCT1 protein co-localizes with MCT2, a neuron-specific Na(+)-independent monocarboxylate transporter. In contrast, there was no overlap of signals for SMCT1 and MCT1, the latter being expressed only in non-neuronal cells. We also demonstrate the neuron-specific expression of SMCT1 in mixed cultures of rat cortical neurons and astrocytes. This represents the first report of an Na(+)-coupled transport system for a major group of energy substrates in neurons. These findings suggest that SMCT1 may play a critical role in the entry of l-lactate and ketone bodies into neurons by a process driven by an electrochemical Na(+) gradient and hence, contribute to the maintenance of the energy status and function of neurons.

Animals↗

PubMed1980

The effects of hypoglycaemia on cerebral blood flow and metabolism in the new-born calf.

1. The effects of insulin hypoglycaemia on cerebral blood flow and metabolism have been examined in unanaesthetized, unrestrained calves between 1 and 26 days after birth. 2. Cerebral blood flow was measured with an inert gas technique using molecular hydrogen, and cerebral metabolism was quantified by determination of arterio-cerebral venous (A--V) concentration differences for oxygen, glucose, lactate, pyruvate, acetoacetate, beta-D-hydroxybutyrate and ammonia. 3. During normoglycaemia the mean (A--V) difference for glucose was close to one sixth that of oxygen, on a molar basis. A small net loss of pyruvate from the brain was found, but there was no significant (A--V) difference for lactate. Arterial concentrations of acetoacetate and beta-D-hydroxybutyrate were low, and no utilization of ketone bodies by the brain was demonstrated. 4. Moderate hypoglycaemia (arterial plasma glucose concentration 1--2 m-mole/l.) had no measurable effect on either cerebral blood flow or metabolism. 5. During profound hypoglycaemia (arterial plasma glucose concentration less than 1.0 m-mole/l.) cerebral glucose uptake was sufficient to account for only 56% of the cerebral oxygen consumption. Cerebral oxygen consumption fell in comatose animals, but increased during hypoglycaemic convulsions, as did cerebral blood flow. 6. In day-old calves hypoglycaemia was associated with a rise in blood lactate concentration and uptake of lactate by the brain. 7. A net loss of ammonia by the brain was observed during hypoglycaemia in calves at all ages examined. The loss was greater in convulsing than in comatose animals.

Ammonia↗