Abstract
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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References
Walter A, Gutknecht J (1984) Monocarboxylic acid permeation through lipid bilayer membranes. J Membr Biol 77:255–264
Alger JR, Prestegard JH (1979) Nuclear magnetic resonance study of acetic acid permeation of large unilamellar vesicle membranes. Biophys J 28:1–13
Klocke RA, Andersson KK, Rotman HH, Forster RE (1972) Permeability of human erythrocytes to ammonia and weak acids. Am J Physiol 222:1004–1013
Sallee VL, Dietschy JM (1973) Determinants of intestinal mucosal uptake of short- and medium-chain fatty acids and alcohols. J Lipid Res 14:475–484
Wolosin JM, Ginsburg H (1975) The permeation of organic acids through lecithin bilayers. Resemblance to diffusion in polymers. Biochim Biophys Acta 389:20–33
Wyss MT, Magistretti PJ, Buck A, Weber B (2011) Labeled acetate as a marker of astrocytic metabolism. J Cereb Blood Flow Metab 31:1668–1674
Muir D, Berl S, Clarke DD (1986) Acetate and fluoroacetate as possible markers for glial metabolism in vivo. Brain Res 380:336–340
Waniewski RA, Martin DL (1998) Preferential utilization of acetate by astrocytes is attributable to transport. J Neurosci 18:5225–5233
Saleh AM, Rudnick H, Aronson PS (1996) Mechanism of H(+)-coupled formate transport in rabbit renal microvillus membranes. Am J Physiol 271:F401–F407
Charney AN, Micic L, Egnor RW (1998) Nonionic diffusion of short-chain fatty acids across rat colon. Am J Physiol 274:G518–G524
Ritzhaupt A, Ellis A, Hosie KB, Shirazi-Beechey SP (1998) The characterization of butyrate transport across pig and human colonic luminal membrane. J Physiol (Lond) 507:819–830
Harig JM, Soergel KH, Barry JA, Ramaswamy K (1991) Transport of propionate by human ileal brush-border membrane vesicles. Am J Physiol 260:G776–G782
Hadjiagapiou C, Schmidt L, Dudeja PK, Layden TJ, Ramaswamy K (2000) Mechanism(s) of butyrate transport in caco-2 cells: role of monocarboxylate transporter 1. Am J Physiol Gastrointest Liver Physiol 279:G775–G780
Stein J, Zores M, Schroder O (2000) Short-chain fatty acid (SCFA) uptake into Caco-2 cells by a pH-dependent and carrier mediated transport mechanism. Eur J Nutr 39:121–125
Halestrap AP, Price NT (1999) The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J 343(Pt 2):281–299
Broer S, Schneider HP, Broer A, Rahman B, Hamprecht B, Deitmer JW (1998) Characterization of the monocarboxylate transporter 1 expressed in Xenopus laevis oocytes by changes in cytosolic pH. Biochem J 333:167–174
Broer S, Broer A, Schneider HP, Stegen C, Halestrap AP, Deitmer JW (1999) Characterization of the high-affinity monocarboxylate transporter MCT2 in Xenopus laevis oocytes. Biochem J 341:529–535
Dimmer KS, Friedrich B, Lang F, Deitmer JW, Broer S (2000) The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells. Biochem J 350:219–227
Grollman EF, Philp NJ, McPhie P, Ward RD, Sauer B (2000) Determination of transport kinetics of chick MCT3 monocarboxylate transporter from retinal pigment epithelium by expression in genetically modified yeast. Biochemistry 39:9351–9357
Manning Fox JE, Meredith D, Halestrap AP (2000) Characterisation of human monocarboxylate transporter 4 substantiates its role in lactic acid efflux from skeletal muscle. J Physiol 529(Pt 2):285–293
Poole RC, Halestrap AP, Price SJ, Levi AJ (1989) The kinetics of transport of lactate and pyruvate into isolated cardiac myocytes from guinea pig. Kinetic evidence for the presence of a carrier distinct from that in erythrocytes and hepatocytes. Biochem J 264:409–418
Poitry-Yamate CL, Poitry S, Tsacopoulos M (1995) Lactate released by Muller glial cells is metabolized by photoreceptors from mammalian retina. J Neurosci 15:5179–5191
Pellerin L (2003) Lactate as a pivotal element in neuron-glia metabolic cooperation. Neurochem Int 43:331–338
Pellerin L, Bergersen LH, Halestrap AP, Pierre K (2005) Cellular and subcellular distribution of monocarboxylate transporters in cultured brain cells and in the adult brain. J Neurosci Res 79:55–64
Whitaker-Menezes D, Martinez-Outschoorn UE, Lin Z, Ertel A, Flomenberg N, Witkiewicz AK, Birbe RC, Howell A, Pavlides S, Gandara R, Pestell RG, Sotgia F, Philp NJ, Lisanti MP (2011) Evidence for a stromal-epithelial “lactate shuttle” in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts. Cell Cycle 10:1772–1783
Martin PM, Gopal E, Ananth S, Zhuang L, Itagaki S, Prasad BM, Smith SB, Prasad PD, Ganapathy V (2006) Identity of SMCT1 (SLC5A8) as a neuron-specific Na + -coupled transporter for active uptake of L-lactate and ketone bodies in the brain. J Neurochem 98:279–288
Carpenter L, Halestrap AP (1994) The kinetics, substrate and inhibitor specificity of the lactate transporter of Ehrlich-Lettre tumour cells studied with the intracellular pH indicator BCECF. Biochem J 304:751–760
Broer S, Rahman B, Pellegri G, Pellerin L, Martin JL, Verleysdonk S, Hamprecht B, Magistretti PJ (1997) Comparison of lactate transport in astroglial cells and monocarboxylate transporter 1 (MCT 1) expressing Xenopus laevis oocytes. Expression of two different monocarboxylate transporters in astroglial cells and neurons. J Biol Chem 272:30096–30102
Wagner CA, Friedrich B, Setiawan I, Lang F, Broer S (2000) The use of Xenopus laevis oocytes for the functional characterization of heterologously expressed membrane proteins. Cell Physiol Biochem 10:1–12
Becker HM, Broer S, Deitmer JW (2004) Facilitated lactate transport by MCT1 when coexpressed with the sodium bicarbonate cotransporter (NBC) in xenopus oocytes. Biophys J 86:235–247
Tosco M, Orsenigo MN, Gastaldi G, Faelli A (2000) An endogenous monocarboxylate transport in Xenopus laevis oocytes. Am J Physiol Regul Integr Comp Physiol 278:R1190–R1195
Deuticke B (1982) Monocarboxylate transport in erythrocytes. J Membr Biol 70:89–103
Poole RC, Halestrap AP (1993) Transport of lactate and other monocarboxylates across mammalian plasma membranes. Am J Physiol 264:C761–C782
Miyauchi S, Gopal E, Fei YJ, Ganapathy V (2004) Functional identification of SLC5A8, a tumor suppressor down-regulated in colon cancer, as a Na(+)-coupled transporter for short-chain fatty acids. J Biol Chem 279:13293–13296
Broer S (2010) Xenopus laevis oocytes. Methods Mol Biol 637:295–310
Dienel GA, Liu K, Cruz NF (2001) Local uptake of (14)C-labeled acetate and butyrate in rat brain in vivo during spreading cortical depression. J Neurosci Res 66:812–820
Nedergaard M, Goldman SA (1993) Carrier-mediated transport of lactic acid in cultured neurons and astrocytes. Am J Physiol 265:R282–R289
Edmond J, Robbins RA, Bergstrom JD, Cole RA, de Vellis J (1987) Capacity for substrate utilization in oxidative metabolism by neurons, astrocytes, and oligodendrocytes from developing brain in primary culture. J Neurosci Res 18:551–561
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Special Issue: In Honor of Leif Hertz.
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Moschen, I., Bröer, A., Galić, S. et al. Significance of Short Chain Fatty Acid Transport by Members of the Monocarboxylate Transporter Family (MCT). Neurochem Res 37, 2562–2568 (2012). https://doi.org/10.1007/s11064-012-0857-3
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DOI: https://doi.org/10.1007/s11064-012-0857-3