Evidence for the existence of enzymatic variants of β-hydroxybutyrate dehydrogenase from rat liver and brain mitochondria

Dombrowski, George J.; Cheung, Geoffrey P.; Swiatek, Kenneth R.

doi:10.1016/0024-3205(77)90164-3

Cited by 10 publications

(5 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3), at least within the range of physiological concentrations during the perinatal period [0.1-2.0 mM l. This result is in agreement with the notion that ketone-body utilization by the tissues depends strictly on their availability in the blood (Hawkins et al, 197 1;Williamson, 1982). The oxidation of 3-hydroxybutyrate by isolated brain cells may be limited by the 3-hydroxybutyrate dehydrogenase (D-3-hydroxybutyrate:NAD+ oxidoreductase; EC 1.1,1.30)-catalyzed reaction because the K,,, of this enzyme in brain [ 1.98 mM (Dombrowski et al, 1977)] is roughly similar to that observed in our experiments on 3-hydroxybutyrate oxidation (Table 1). In addition, during the perinatal period 3-hydroxy- butyrate dehydrogenase activity is lower than that of other enzymes involved in ketone-body utilization (Page et al, 197 1;Booth et al, 1980), a fact consistent with the idea that ketone-body oxidation during the early postnatal period could be limited by the 3-hydroxybutyrate dehydrogenase-catalyzed reaction.…”

Section: Discussionsupporting

confidence: 83%

Lactate Utilization by Isolated Cells from Early Neonatal Rat Brain

Vicario‐Abejón

Arizmendi

Malloch

et al. 1991

Journal of Neurochemistry

View full text Add to dashboard Cite

The utilization of lactate, glucose, 3-hydroxybutyrate, and glutamine has been studied in isolated brain cells from early newborn rats. Isolated brain cells actively utilized these substrates, showing saturation at concentrations near physiological levels during the perinatal period. The rate of lactate utilization was 2.5-fold greater than that observed for glucose, 3-hydroxybutyrate, or glutamine, suggesting that lactate is the main metabolic substrate for the brain immediately after birth. The apparent Km for glucose utilization suggested that this process is limited by the activity of hexokinase. However, lactate, 3-hydroxybutyrate, and glutamine utilization seems to be limited by their transport through the plasma membrane. The presence of fatty acid-free bovine serum albumin (BSA) in the incubation medium significantly increased the rate of lipogenesis from lactate or 3-hydroxybutyrate, although this was balanced by the decrease in their rates of oxidation in the same circumstances. BSA did not affect the rate of glucose utilization. The effect of BSA was due not to the removal of free fatty acid, but possibly to the binding of long-chain acyl-CoA, resulting in the disinhibition of acetyl-CoA carboxylase and citrate carrier.

show abstract

Section: Discussionsupporting

confidence: 83%

Lactate Utilization by Isolated Cells from Early Neonatal Rat Brain

Vicario‐Abejón

Arizmendi

Malloch

et al. 1991

Journal of Neurochemistry

View full text Add to dashboard Cite

show abstract

“…This is corroborated by a precedent work in which we proposed a molecular mechanism of BDH catalysis in the liver and in the peripheral tissues based on BDH conformational change [22]. Such a hypothesis has also been reported earlier in rat model, for the liver and the brain BDH [35] as well as in the goldfish model, Carassius auratus for liver and kidney BDH [36]. …”

Section: Discussionsupporting

confidence: 84%

Hibernation impact on the catalytic activities of the mitochondrial D-3-hydroxybutyrate dehydrogenase in liver and brain tissues of jerboa (Jaculus orientalis)

et al. 2003

View full text Add to dashboard Cite

BackgroundJerboa (Jaculus orientalis) is a deep hibernating rodent native to subdesert highlands. During hibernation, a high level of ketone bodies i.e. acetoacetate (AcAc) and D-3-hydroxybutyrate (BOH) are produced in liver, which are used in brain as energetic fuel. These compounds are bioconverted by mitochondrial D-3-hydroxybutyrate dehydrogenase (BDH) E.C. 1.1.1.30. Here we report, the function and the expression of BDH in terms of catalytic activities, kinetic parameters, levels of protein and mRNA in both tissues i.e brain and liver, in relation to the hibernating process.ResultsWe found that: 1/ In euthemic jerboa the specific activity in liver is 2.4- and 6.4- fold higher than in brain, respectively for AcAc reduction and for BOH oxidation. The same differences were found in the hibernation state. 2/ In euthermic jerboa, the Michaelis constants, KM BOH and KM NAD+ are different in liver and in brain while KM AcAc, KM NADH and the dissociation constants, KD NAD+and KD NADH are similar. 3/ During prehibernating state, as compared to euthermic state, the liver BDH activity is reduced by half, while kinetic constants are strongly increased except KD NAD+. 4/ During hibernating state, BDH activity is significantly enhanced, moreover, kinetic constants (KM and KD) are strongly modified as compared to the euthermic state; i.e. KD NAD+ in liver and KM AcAc in brain decrease 5 and 3 times respectively, while KD NADH in brain strongly increases up to 5.6 fold. 5/ Both protein content and mRNA level of BDH remain unchanged during the cold adaptation process.ConclusionsThese results cumulatively explained and are consistent with the existence of two BDH enzymatic forms in the liver and the brain. The apoenzyme would be subjected to differential conformational folding depending on the hibernation state. This regulation could be a result of either post-translational modifications and/or a modification of the mitochondrial membrane state, taking into account that BDH activity is phospholipid-dependent.

show abstract

“…Significantly, the peak rate of ketone body utilization, 1.75 Â V AcCoA-kb(N þ A) /2 ¼ 0.47 mmol/g per minute, is approximately one-third of the V max -like activity of BHB dehydrogenase (B1.2 to 1.4 mmol/g per minute after correction to a physiologic temperature of 37 1C from 25 1C assuming Q 10 ¼ 2), the least enzymatically active of the three pathway enzymes supporting ketone body oxidation, [31][32][33][34] as measured in rat cortex homogenate in vitro. 31 Because brain AcAc concentration determines the rate of ketone body oxidation, 31 and brain BHB levels at the rate saturation of B1.7 mM ( Figure 5) were comparable with the in vitro K m of BHB dehydrogenase for BHB (B2 mM), 35,36 the saturation of this rate is not readily explained, but compartmentation and mitochondrial transport, or physiologic concentrations of cofactors (e.g., NAD þ (nicotinamide adenine dinucleotide)) might be involved. Interestingly, the estimated maximum rate of ketone body oxidation in the awake rat cortex of B59% is similar to the global average of 58% to 60% measured by arteriovenous difference under conscious sedation in three obese subjects after 38 to 41 days of starvation, 37 extreme adaptive conditions where transport is not likely to be limiting for brain ketone consumption.…”

Section: Discussionmentioning

confidence: 66%

The Contribution of Ketone Bodies to Basal and Activity-Dependent Neuronal Oxidation in Vivo

Chowdhury

Jiang

Rothman

et al. 2014

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

The capacity of ketone bodies to replace glucose in support of neuronal function is unresolved. Here, we determined the contributions of glucose and ketone bodies to neocortical oxidative metabolism over a large range of brain activity in rats fasted 36 hours and infused intravenously with [2,4-13 C 2 ]-D-b-hydroxybutyrate (BHB). Three animal groups and conditions were studied: awake ex vivo, pentobarbital-induced isoelectricity ex vivo, and halothane-anesthetized in vivo, the latter data reanalyzed from a recent study. Rates of neuronal acetyl-CoA oxidation from ketone bodies (V acCoA-kbN ) and pyruvate (V pdhN ), and the glutamateglutamine cycle (V cyc ) were determined by metabolic modeling of 13 C label trapped in major brain amino acid pools. V acCoA-kbN increased gradually with increasing activity, as compared with the steeper change in tricarboxylic acid (TCA) cycle rate (V tcaN ), supporting a decreasing percentage of neuronal ketone oxidation: B100% (isoelectricity), 56% (halothane anesthesia), 36% (awake) with the BHB plasma levels achieved in our experiments (6 to 13 mM). In awake animals ketone oxidation reached saturation for blood levels 417 mM, accounting for 62% of neuronal substrate oxidation, the remainder (38%) provided by glucose. We conclude that ketone bodies present at sufficient concentration to saturate metabolism provides full support of basal (housekeeping) energy needs and up to approximately half of the activity-dependent oxidative needs of neurons. Keywords: 13 C isotopes; glucose utilization; glutamate/glutamine cycle; ketone body utilization; neuroenergetics; nuclear magnetic resonance spectroscopy INTRODUCTIONThe adult mammalian brain shows a remarkably high utilization of glucose compared with other potential fuel substrates, such as lactate or ketone bodies. Brain consumption of alternate substrates is limited by transport from the blood, and factors which alter membrane transport alter the rate of consumption. Under fasting conditions, starvation, or diets high in fats, blood ketone body levels rise, increasing their cerebral rate of consumption. The extent to which ketone bodies can support the different aspects of brain function, once transport is no longer limiting, has not been clearly established. Ketone bodies are metabolized by neurons and astrocytes in vitro and in vivo, 1-3 and like glucose, neuronal (glutamatergic) oxidation dominates quantitatively in vivo, 3,4 reflecting the relatively larger volume fraction of neurons compared with glial cells. Despite extensive study to ascertain the role of ketone bodies in neural function, basic unanswered questions persist about their involvement, and that of glucose, in the energy requirements associated with neurotransmission.Previous studies from our laboratory using 13 C magnetic resonance spectroscopy (MRS) with [1-13 C]glucose reported a linear relationship between neuronal oxidation of glucose in the tricarboxylic acid (TCA) cycle and glutamate (Glu)-glutamine (Gln) cycling flux over a large range of brain activity, 5-7...

show abstract

Evidence for the existence of enzymatic variants of β-hydroxybutyrate dehydrogenase from rat liver and brain mitochondria

Cited by 10 publications

References 13 publications

Lactate Utilization by Isolated Cells from Early Neonatal Rat Brain

Lactate Utilization by Isolated Cells from Early Neonatal Rat Brain

Hibernation impact on the catalytic activities of the mitochondrial D-3-hydroxybutyrate dehydrogenase in liver and brain tissues of jerboa (Jaculus orientalis)

The Contribution of Ketone Bodies to Basal and Activity-Dependent Neuronal Oxidation in Vivo

Contact Info

Product

Resources

About