Lactate as an energy source of the brain ?
Fenny L. Yudiarto
Mardi Rahayu Hospital, Kudus-Central Java, Indonesia.
Abstract
Lactate has no longer mentioned as a useless product but has been studied as a substrate that very important for neuron. Brain tissue produces lactate under aerobic conditions and demonstrates the ability of this tissue to respire. Many researches supported that lactate is preferred substrate over glucose whether aerobic or anaerobic condition, under rest or during activation.
Astrocytes produce lactate from glycolysis (lactate source) but can not uptake lactate from extracellular or from neurons, contrast with neurons. Neurons can produce lactate from glycolysis in resting state, but mostly receive lactate from glial during activation (lactate sink). This process is due to different MCT between neurons and astrocytes.
Neuronal damaged post ischemia is not due by lactate production but because of the increase level of corticosterone few hours post ischemia. Lactate exogenously have different metabolism with endogenously lactate. Hence, it will decrease PH extracellular and can make neuronal death.
Keywords: Lactate, glial glycolytic, MCT
Introduction
The brain is an organ with high energy demands, it represents only 2% of the body weight, but it contributes up to 20% of its resting metabolism (Magistretti et al., 1999a). For the functional of the brain needs three cells which collaborate to perform complex tasks, they are neurons, glial cells and vascular cells. Blood vessels are linked to neuronal functioning through the process named as neurovascular coupling and for synaptic activity need neurometabolic coupling, a complex team works between neuron and glial cells (Leybaert., 2005).
Glucose is considered to the most useful energy substrate for neuronal activity. Glucose utilization based on molecular mechanism that involve the sequential intervention of astrocyte-specific glutamate transporters and sodium-potassium ATPase, activation of glycolisis in astrocytes and monocarboxylate transporter-mediated exchange of lactate from astrocytes to neuron (Magistretti et al., 1999b).
For many years, most scientist agreed that lactate is a useless end product of anaerobic energy metabolism, which at time can become harmful. In the brain, lactate has been romoted as a major exacerbating factor of cerebral ischemic damage. On 1994 Pellerin and Magistretti proposed a hypothesis about astrocyte-neuron lactate shuttle (ANLSH), this hypothesis described about the role of lactate in cerebral (and other tissues) as an energy source for metabolism and lactate plays as important a role in cerebral oxidative energy metabolism as does glucose (Pellerin et al., 1994).
Neuron-glial glutamate-glutamine cycle
Glutamate (Glu) is the major excitatory neurotransmitter, constitutes more than 90% cortical neuron in adult brain (Nicholls., 1993). Glu is also a precursor of GABA so Glu metabolism plays a central role in glutamatergic and GABAergic function. Glu has concentration differs in these cell types; glutamatergic neurons possess 80% - 88%, whereas GABAergic neuron contain 2%-10% and astrocytes 10% of total tissue glutamate (Lebon et al., 2002).
Glu released from glutamatergic synapses into the extracellular space during synaptic activity is taken up by the astrocytes, in co transport with sodium, thereby increasing intracellular sodium stimulating the sodium-potassium pump (Pellerin et al., 1997). It is importance to maintain the extracellular Glu concentration keeping low and up taking Glu needs a lot of ATP consumption and drives glycolysis to back up the cellular ATP content, the product of glycolysis is lactate (Schurr et al., 1999). In astrocytes Glu will convert to glutamine (Gln) which is released to the extracellular fluid, and then will be taken up by neuron. The trafficking of Glu and Gln between astrocytes and neuron have been proposed to be a major pathway by which transmitter Glu recycled, it is commonly named as glutamate-glutamine cycle (Danbolt., 2001)
Glucose and lactate metabolism on the brain
Besides neurometabolic coupling, neurovascular coupling is the other physiological response of the brain. Astrocytes have an important role on those coupling. First, on neuronal activation, astrocytes take up the released Glu via calsium-dependent mechanism (Magistretti., 2006). Second, astrocytes regulate microarteriole tone through a mechanism involving a pulsatile release of prostaglandins evoked by Glu-induced calsium oscillations (Bonvento et al., 2005).
For many years, elevated tissue lactate levels have been considered to signal the existence of hypoxia and anaerobic energy metabolism. Although substantial evidence has been proved to indicate that large amounts of lactate can be produced in many tissue under aerobic conditions. Many studies now suggest that the brain is not necessarily different from other tissues, because it does produce lactate aerobically when stimulated in both human and animal (Schurr et al., 1999). On 1994 Pellerin and Magistretti proposed a hypothesis known as the Astrocyte-Neuron Lactate Shuttle Hypothesis (ANLSH) awakened neuroscientists that lactate plays as important a role in cerebral oxidative energy metabolism as glucose.
When neuronal activation stimulated by glutamate (Glu), astrocytes will take up presynaptically released Glu from the synaptic cleft through specific Na+-dependent Glu transporters. The result is increase Na+ in astrocytes induce Na-K-ATPase activity to pump out the extra Na+. The increased demand for ATP by the pumping activity will stimulate astrocytic glycolysis and thus the production of lactate (Gladden., 2004).
Lactate mainly produced and released from astrocytes, can function as a cellular energy substrate with lower ATP requirement (Schurr., 2006). Lactate transport across membranes requires monocarboxylate transportes (MCT), 14 MCT isoforms have been identified in mammals and hydrophyllic substances (Pierre et al., 2005). MCT1 is highly expressed in astrocytes, whereas MCT2 is prevalent in neurons (Pierre et al., 2000) (Table.1). Lactate taken up by neurons can be converted to pyruvate and directly enters tricarboxylic acid (TCA) cycle to generate energy. The various LDH isoenzymes reversibly convert pyruvate to lactate with different specificity. Astrocytes mainly express LDH5 which favors the conversion of pyruvate to lactate. Neurons primarily contain LDH1 direct convert pyruvate to form lactate via TCA cycle (Chih et al., 2001). (Fig. 2). LDH5 reveals higher expressed in grey matter than white matter and pyruvate dehydrogenase (PDH) very little shown in the white matter (Laughton et al., 2007).
Table 1. Distinct metabolic preferences between astrocytes and neurons
| | Neurons | Astrocytes |
| Glucose transporter (1) | GLUT3 | GLUT1 lower intrinsic rate of transport but higher affinity |
| Lactate dehydrogenase (2) | LDH1 (mitochondrial) | LDH5 (cytoplasmic) |
| Monocarboxylate transporters (3,4) | MCT2 high affinity | MCT1 and MCT4 low affinity |
| Lactate metabolism (5) | Lactate sink | Lactate source |
| Metabolic profile (6) | Highly oxidative | Glycolytic capacity |
| Predominance (7) | TCA cycle more important | Glutamate-glutamine cyc |
GLUT= glucose transporter, LDH= Lactate dehydrogenase, MCT= Monocarboxylate transporter, TCA= tricarboxylate acid. (1)= Vannucci et al., 1997, (2)= Bittar et al., 1996, (3,4)= Rafiki et la., 2003, Pellerin et al., 2005. (5)= Pellerin et al., 1998, (6)= Pellerin et al., 1998. (7)= Bouzier-sore et al., 2006
MCTs are involved in the uptake and release of lactate, pyruvate, and ketone bodies. MCT1 was strongly expressed by astrocytes both in vivo and in vitro, it as also found at high level on endothelial cells of blood vessels, ependymocytes and microglial, MCT4 was exclusively in astrocytes. MCT2 expressed in cultured neurons and located in postsynaptic densities (Pierre et al., 2005, Pellerin et al., 2005).
MCT2 expression could be linked with the development of synapses or synaptic activity because increase MCT2 concomitantly followed by the expression of synaptophysin in dendrites spines (Bergersen et al., 2004) (Fig. 3). Noradrenaline can also induce the expression of MCT2 but not MCT1 in culture neurons via translational regulation (Pierre et al., 2003). Boosting neuroenergetics by enhancing the lactate and favoring lactate utilization by neurons has been considered as a important strategy for neuroprotection against excitotoxicity (Sapolsky., 2003)
Astrocytes consume large amounts of glucose and produce large quantities of lactate. In comparison, neurons consume less glucose than astrocytes and proportionally produce much less lactate. Ratio of lactate produced/glucose consumed is above 1 in astrocytes and lower than 1 for neurons (1.6 and 0.6) (Bouzier-Sore., 2006). Under physiological conditions lactate is a better neuronal oxidative energy substrate compare with glucose. Utilization of one of the two substrate is reduced by utilization of the other, in such condition if a small reduction in lactate utilization would also followed by slightly more glucose utilization (Cerdan et al., 2006).
Lactate on brain ischemia: harmful or benefit?
Glucose has been promoted as energy substrate in the brain under normoxic conditions, on the stroke infarction when glucose administered shortly preischemia (15 – 60 minutes), an aggravation of the ischemic outcome was observed. But when it administered 2-3 hours pre-ischemia, the presence of hyperglycemic conditions had no aggravation of outcome. Hence glucose per se is unlikely aggravator of ischemic damage (Schurr., 2002). Another study from Schurr revealed that corticosteroid levels as a stress hormone had sharp increase after 15 – 30 minutes after glucose administration, followed by a return to baseline level 120 minutes after glucose infusion. These changes appear to have correlation with neuronal damage (Schurr et al., 2001a).
Some studies recently showed that delayed neuronal damage was not directly correlated with brain lactate level. Schurr et al 2001 found that inhibition of lactate utilization immediately postischemia is detrimental (Schurr et al., 2001b). Lactate can be detected 30-90 minutes after reperfusion (Li et al., 1997). Lactate probably remained unused due to cell death. Neither glucose nor lactate appears to be the damaging factor during cerebral ischemia.
There is no evidence to suggest that lactate itself is harmful to tissue, the low PH associated with lactate accumulation can directly disrupt cell membrane, leading cell death within 30 minutes. With exposure to more moderate acidity, cell death occurs with a latency of as long as 24 – 48 hours. Astrocytes contribute 6.3 times as much lactate as neuron under normal condition, it will increase 7.7 fold in normoglicemic ischemia and to 12.2 fold with hyperglycemic ischemia. The increase lactate production will reduce the PH (Baowan Lin et al., 1995).
Mitochondrial LDH1 is the enzyme that dehydrogenates lactate to pyruvate, and cytosolic LDH5 have a role on glycolytic lactate formation. LDH5-catalyzed formation of lactate assure the oxidation of NADH and NAD+ reduction to NADH during lactate oxidation takes place in the mitochondrion and should have little or no effect on cytosolic glycolysis. Glycolytically produced pyruvate is predominantly converted to lactate, not to acetyl-CoA, while lactate exogenously is preferentially oxidized to acetyl-CoA (Brook., 2002).
Pyruvate level is always lower than lactate and the ratio [lactate]/ [pyruvate] is 7.0-25.0 depending on the conditions. The low end of this ratio usually associated with pathological situations (Schurr., 2006). Lactate is metabolized to CO2 more rapidly in synaptosomes than in astrocytes, And acetate is metabolized to CO2 more rapidly in astrocytes than in synaptosomes. This is likely due to cellular differences in the expression of monocarboxylate transporter subtypes (Waniewski et al., 2004). Extracellular lactate accumulation during and after ischemia is not crucial determinant of differences in ischemic outcome, neuroprotective influence can not be attributed to the attenuation of cerebral lactate accumulation on extracellularly.
On ischemia period, level of glucose will increase on brain tissue due to drop in its utilization, lactate also rises after 60 seconds of ischemia, and this is indicated that the rate of lactate production exceeds its rate of utilization. When lactate supplied exogenously, is an oxidative substrate for the mitochondrial TCA cycle, and inhibits the glycolytic utilization of glucose (will decrease the need of ATP) (Hertz., 2004). Under certain conditions, it was shown that astrocytes can use some lactate as an energy substrate, but much lesser extent than neurons and oligodendrocytes. They can utilize lactate as a precursor for gluconeogenesis and glycogen synthesis (Waniewski et al., 2004).
The response or adaptation of the brain is different during acute hypoxia and long-term hypoxia. On the acute hypoxic condition (over 1 day), studied by Vega found the expression of sodium-independent, sodium-dependent glucose transporters, astrocytic monocarboxylate transporter isoform (MCT), and increase both glycolytic activity and also lactate released by astrocytes. In contrast, the expression of these transporters decreased depletion of energy consumption (metabolic depression) after 3 weeks of hypoxia (Vega et al., 2006). The shift from glycolytic strategy to metabolic depression strategy is to sustain cellular ATP levels in the absence of oxygen.
To cope with long-term hypoxia, astrocytes may decrease extracellular glucose uptake and lactate release to the expense of neuronal metabolic coupling to ensure their own energy supply from glycogen stores and maintain mitochondrial function. Consequently energy substrate availability for neuron would be significantly reduced, to allow the fueling of astrocytic oxidative metabolism and ATP formation for their own survival. This is a part of adaptive mechanism to long-term hypoxia and may explain the relatively higher neuronal susceptibility to hypoxia compared with astrocytes (Almeida et al., 2002, Wang et al., 2002). Furthermore, this astrocytic strategy of preserving glial over surrounding cells may be essential in long-term neural tissue recovery from hypoxic challenges; surviving astrocytes may be required to provide energy for surrounding tissue recovery (Vega et al., 2006). Within the central nervous system the susceptibility to hypoxia has been noted to vary in the different cell types. By with astrocytes and endothelial cells more capable of withstanding hypoxic injury compared than neurons and oligodendrocytes (Xu et al., 2001).
Astrocytes are an important intermediary between capillaries, neurons, and the synapses of the neurons (Magistretti et al., 1999), the entire surface of interparenchymal capillaries is covered by specialized astrocytic end-feet (Bushong et al., 2002) and the astrocyte : neuron ratio is 10 : 1 (Bignami., 1991). MCT1, MCT4 specifically on astrocytes, are transporters which release lactate into extracellular space, and also LDH5 which convert pyruvate to lactate. This evidence explains that astrocytes can not use lactate exogenous as energy source.
MCT2 overexpression did not enhance lactate utilization. However higher concentration of lactate are reported to stimulate neuronal lactate utilization (Itoh et al., 2003), but MCT2 overexpression enhance neuronal survival after exposure to glutamate, because glutamate decrease cell energy status (Nicholl et al., 1998). Bliss et al (2004) found that overexpression GLUT1 in glia was neuroprotective. This overexpression will enhance both glucose utilization and lactate release. GLUT1 overexpression alters regulation of glycolytic enzymes and enhances glutamate-induced lactate formation in glia. The presence of glia overexpressing GLUT1 make glutamate was less toxic to neurons ( Bliss et al., 2004).
Some studies which against and support ANLS?
Studies which support the ANLS
- Neuronal tissue can use lactate as a fuel and may prefer it.
- Study on sympathetic ganglia has reported lactate utilization in replacement of glucose (Brown et al., 2001)
- Lactate can substitute, or is preferred to glucose, in cultured cortical neurons (Bouzier-Sore et al., 2003), human brain in vivo (Smith et al., 2003)
- LDH1 is predominant in neurons convert lactate to pyruvate, LDH5 is predominant isoform in astrocytes, convert pyruvate to lactate (Pellerin et al., 1998).
- Nuclear Magnetic resonance spectroscopy has provided of lactate utilization as an energy substrate in brain tissue, specifically as a neuronal fuel (Hassel et al., 2000, Qu et al., 2000)
- Na+-K+-ATPase is expressed together with Glu transporter (GLT-1 and GLAST) in astrocytic processes surrounding glutamatergic synapses. Glu is the primary excitatory neurotransmitter of the cerebral cortex, astrocytic glutamatergic activity will produce and release lactate (
- In cultures mouse astrocytes uptake Glu is strongly associated with increased lactate production and equal with the rate of glial glutamate cycling (Pellerin et al., 1994).
Studies which against ANLS
- Neuronal glucose transporter GLUT3 is much faster than the primary glial transporter GLUT1. Why neural activity either in situ or in vivo should activate glial glycolysis but not neuronal glycolysis (Chih et al., 2001)
- Some studies find that astrocytic metabolism is not particularly less oxidative than the metabolism of neurons, neurons can use pyruvate directly from neuronal glycolysis rather than from astrocytic glycolysis (Gjedde et al., 2001).
Accumulation of lactate and increase the level of adenosine during hypoxic ischemia will inhibit glucose uptake and block to glucose transporter (Bliss., 2001), So even GLUT3 much faster than GLUT1, those transporter can not work well during ischemia.
Conclusion
Lactate is an aerobic energy substrate on the brain, neuronal damage post ischemia has not been due to lactate or glucose accumulation, but rather than increase level of corticosteron on the early phase of ischemia or because of the decrease of blood PH.
Astrocytes have different both MCT and LDH with neurons. MCT1, MCT4 bring lactate from astrocyte into extracellular. Contrast to neurons, MCT2 will uptake lactate from extracellular and LDH1 will convert to pyruvate then directly enter to TCA.
Many studies showed against and support the hypothesis of ANLS, but lactate seems a good energy source besides glucose for neurons and astrocytes, but only neuron can use lactate from extracellular.
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