Significance of Short Chain Fatty Acid Transport by Members of the Monocarboxylate Transporter Family (MCT)

Physiologisches Institut, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany.
Neurochemical Research (Impact Factor: 2.59). 08/2012; 37(11). DOI: 10.1007/s11064-012-0857-3
Source: PubMed


Metabolism of short-chain fatty acids (SCFA) in the brain, particularly that of acetate, appears to occur mainly in astrocytes. The differential use has been attributed to transport, but the extent to which transmembrane movement of SCFA is mediated by transporters has not been investigated systematically. Here we tested the possible contribution of monocarboxylate transporters to SCFA uptake by measuring fluxes with labelled compounds and by following changes of the intracellular pH in Xenopus laevis oocytes expressing the isoforms MCT1, MCT2 or MCT4. All isoforms mediated significant transport of acetate. Formate, however, was transported only by MCT1. The contribution of MCT1 to SCFA transport was determined by using phloretin as a high-affinity inhibitor, which allowed a paired comparison of oocytes with and without active MCT1.

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Available from: Stefan Bröer, Oct 07, 2015
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    • "The underlying reason for this difference might be a poor export of formate from cultured neurons and/or a higher capacity of these cells to further oxidize formate to carbon dioxide (Fig. 1). Although the putative formate exporters, GABAgated channels (Mason et al. 1990) and monocarboxylate transporter (MCT) 1 (Moschen et al. 2012) are expressed in both astrocytes and neurons (Debernardi et al. 2003; Olsen and Sieghart 2009; Lee et al. 2011; Velez-Fort et al. 2011), the expression level of MCT1 in neurons has been reported to be very low (Debernardi et al. 2003). However, if poor export of formate would be the only reason behind the lower extracellular accumulation of this metabolite in cultured neurons, these cells should accumulate large amounts of formaldehyde-derived formate, which is not the case (Tulpule et al. 2013). "
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    ABSTRACT: Formaldehyde is an environmental pollutant that is also generated in substantial amounts in the human body during normal metabolism. This aldehyde is a well-established neurotoxin that affects memory, learning, and behavior. In addition, in several pathological conditions, including Alzheimer's disease, an increase in the expression of formaldehyde-generating enzymes and elevated levels of formaldehyde in brain have been reported. This article gives an overview on the current knowledge on the generation and metabolism of formaldehyde in brain cells as well as on formaldehyde-induced alterations in metabolic processes. Brain cells have the potential to generate and to dispose formaldehyde. In culture, both astrocytes and neurons efficiently oxidize formaldehyde to formate which can be exported or further oxidized. Although moderate concentrations of formaldehyde are not acutely toxic for brain cells, exposure to formaldehyde severely affects their metabolism as demonstrated by the formaldehyde-induced acceleration of glycolytic flux and by the rapid multidrug resistance protein 1-mediated export of glutathione from both astrocytes and neurons. These formaldehyde-induced alterations in the metabolism of brain cells may contribute to the impaired cognitive performance observed after formaldehyde exposure and to the neurodegeneration in diseases that are associated with increased formaldehyde levels in brain. The neurotoxin formaldehyde is an environmental pollutant that is also generated during normal brain metabolism. The levels of formaldehyde in brain increase with age and in some neurodegenerative disorders. As excess formaldehyde accelerates glycolysis and glutathione export in neural cells, formaldehyde-induced alterations in brain metabolism and oxidative stress may contribute to the pathological progression of neurodegenerative disorders.
    Preview · Article · Jun 2013 · Journal of Neurochemistry
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    • "In this context, acetate has been found to be a good substrate for neuronal MCT2 (Rae et al. 2012). Moreover, acetate is transported by MCT2 in Xenopus laevis oocytes expressing the MCT2 isoform (Moschen et al. 2012). Therefore, the membrane localization of MCT2 in the various parts of the cattle gastrointestinal tissues examined in the current study strongly suggests its contribution to the influx and/or efflux of short-chain fatty acids across the gastrointestinal epithelia; additionally, it might be involved in the regulation of gastric secretion. "
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    ABSTRACT: Fourteen members of the monocarboxylate transporter (MCT, SLC16) family have been identified, each having a different tissue distribution and substrate specificity. The expression of monocarboxylate transporters MCT1 and MCT4 have been studied in the gastrointestinal tract of ruminants; however, details of the expression of other MCT isoforms in the various parts of ruminant gastrointestinal tract are lacking. Reverse transcription with the polymerase chain reaction was used to study the regional distribution of MCT2, MCT3, and MCT5-MCT14 in the cattle gastrointestinal tract and verified the existence of MCT mRNA transcripts for MCT2, MCT3, MCT4, MCT7, MCT8, MCT9, MCT10, MCT13, and MCT14 in the ruminal and abomasal epithelia, mRNA transcripts for MCT2, MCT3, MCT4, MCT7, MCT8, MCT10, MCT13, and MCT14 in the jejunum, and mRNA transcripts for MCT2, MCT3, MCT4, MCT7, MCT8, MCT13, and MCT14 in the caecum of cattle. At the cellular level, immunohistochemical studies localized MCT2, MCT7, and MCT8 proteins in the cattle rumen, abomasum, jejunum, and caecum. This is the first study to detect the expression of various MCT isoforms in the gastrointestinal tract of a ruminant species. Our data suggest that these transporter proteins are involved in essential physiologic processes and are possible molecular targets for studying the regulation of the transport of short-chain monocarboxylates, aromatic amino acids, and thyroid hormones across the gastrointestinal tract of cattle.
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    • "Neurons are known to express monocarboxylic acid transporters (Pierre and Pellerin, 2005) and the activity of acetyl-CoA synthetase, the enzyme responsible for acetate utilization, is higher in synaptosomes (Waniewski and Martin, 1998) suggesting that neurons can also utilize acetate. This is substantiated by studies demonstrating that neuronal MCT2 transports acetate with affinities comparable to that of astrocytic MCT1 (km $1.6–2.5 mM) (Rae et al., 2012), although acetate transport by MCT2 may be limited in presence of lactate similar to that found with the sodium-dependent MCT1 (Moschen et al., 2012). On the other hand, Brand et al. demonstrated that acetate can be metabolized by both the cell types and that in neurons acetate-derived labeled carbon is recovered as glutamate and aspartate while in astrocytes as glutamine (Brand et al., 1997). "
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    ABSTRACT: Acetate supplementation in rats increases plasma acetate and brain acetyl-CoA levels. Although acetate is used as a marker to study glial energy metabolism, the effect that acetate supplementation has on normal brain energy stores has not been quantified. To determine the effect(s) that an increase in acetyl-CoA levels has on brain energy metabolism, we measured brain nucleotide, phosphagen and glycogen levels, and quantified cardiolipin content and mitochondrial number in rats subjected to acetate supplementation. Acetate supplementation was induced with glyceryl triacetate (GTA) by oral gavage (6 g/Kg body weight). Rats used for biochemical analysis were euthanized using head-focused microwave irradiation at 2, and 4 hr following treatment to immediately stop metabolism. We found that acetate did not alter brain ATP, ADP, NAD, GTP levels, or the energy charge ratio [ECR, (ATP + ½ ADP) / (ATP + ADP + AMP)] when compared to controls. However, after 4 hr of treatment brain phosphocreatine levels were significantly elevated with a concomitant reduction in AMP levels with no change in glycogen levels. In parallel studies where rats were treated with GTA for 28 days, we found that acetate did not alter brain glycogen and mitochondrial biogenesis as determined by measuring brain cardiolipin content, the fatty acid composition of cardiolipin and using quantitative ultra-structural analysis to determine mitochondrial density/unit area of cytoplasm in hippocampal CA3 neurons. Collectively, these data suggest that an increase in brain acetyl-CoA levels by acetate supplementation does increase brain energy stores however it has no effect on brain glycogen and neuronal mitochondrial biogenesis.
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