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1
DIMMER, Kai-Stefan, Björn FRIEDRICH, Florian LANG, Joachim W. DEITMER, and Stefan BRÖER. "The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells." Biochemical Journal 350, no. 1 (August 9, 2000): 219–27. http://dx.doi.org/10.1042/bj3500219.
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Transport of lactate and other monocarboxylates in mammalian cells is mediated by a family of transporters, designated monocarboxylate transporters (MCTs). The MCT4 member of this family has recently been identified as the major isoform of white muscle cells, mediating lactate efflux out of glycolytically active myocytes [Wilson, Jackson, Heddle, Price, Pilegaard, Juel, Bonen, Montgomery, Hutter and Halestrap (1998) J. Biol. Chem. 273, 15920–15926]. To analyse the functional properties of this transporter, rat MCT4 was expressed in Xenopus laevis oocytes and transport activity was monitored by flux measurements with radioactive tracers and by changes of the cytosolic pH using pH-sensitive microelectrodes. Similar to other members of this family, monocarboxylate transport via MCT4 is accompanied by the transport of H+ across the plasma membrane. Uptake of lactate strongly increased with decreasing extracellular pH, which resulted from a concomitant drop in the Km value. MCT4 could be distinguished from the other isoforms mainly in two respects. First, MCT4 is a low-affinity MCT: for l-lactate Km values of 17±3mM (pH-electrode) and 34±5mM (flux measurements with l-[U-14C]lactate) were determined. Secondly, lactate is the preferred substrate of MCT4. Km values of other monocarboxylates were either similar to the Km value for lactate (pyruvate, 2-oxoisohexanoate, 2-oxoisopentanoate, acetoacetate) or displayed much lower affinity for the transporter (β-hydroxybutyrate and short-chain fatty acids). Under physiological conditions, rat MCT will therefore preferentially transport lactate. Monocarboxylate transport via MCT4 could be competitively inhibited by α-cyano-4-hydroxycinnamate, phloretin and partly by 4,4´-di-isothiocyanostilbene-2,2´-disulphonic acid. Similar to MCT1, monocarboxylate transport via MCT4 was sensitive to inhibition by the thiol reagent p-chloromercuribenzoesulphonic acid.
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Becker, Helen M., Nilufar Mohebbi, Angelica Perna, Vadivel Ganapathy, Giovambattista Capasso, and Carsten A. Wagner. "Localization of members of MCT monocarboxylate transporter family Slc16 in the kidney and regulation during metabolic acidosis." American Journal of Physiology-Renal Physiology 299, no. 1 (July 2010): F141—F154. http://dx.doi.org/10.1152/ajprenal.00488.2009.
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The monocarboxylate transporter family (MCT) comprises 14 members with distinct transport properties and tissue distribution. The kidney expresses several members of the MCT family, but only little is known about their exact distribution and function. Here, we investigated selected members of the MCT family in the mouse kidney. MCT1, MCT2, MCT7, and MCT8 localized to basolateral membranes of the epithelial cells lining the nephron. MCT1 and MCT8 were detected in proximal tubule cells whereas MCT7 and MCT2 were located in the thick ascending limb and the distal tubule. CD147, a β-subunit of MCT1 and MCT4, showed partially overlapping expression with MCT1 and MCT2. However, CD147 was also found in intercalated cells. We also detected SMCT1 and SMCT2, two Na+-dependent monocarboxylate cotransporters, on the luminal membrane of type A intercalated cells. Moreover, mice were given an acid load for 2 and 7 days. Acidotic animals showed a marked but transient increase in urinary lactate excretion. During acidosis, a downregulation of MCT1, MCT8, and SMCT2 was observed at the mRNA level, whereas MCT7 and SMCT1 showed increased mRNA abundance. Only MCT7 showed lower protein abundance whereas all other transporters remained unchanged. In summary, we describe for the first time the localization of various MCT transporters in mammalian kidney and demonstrate that metabolic acidosis induces a transient increase in urinary lactate excretion paralleled by lower MCT7 protein expression.
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Wang, X., A. J. Levi, and A. P. Halestrap. "Substrate and inhibitor specificities of the monocarboxylate transporters of single rat heart cells." American Journal of Physiology-Heart and Circulatory Physiology 270, no. 2 (February 1, 1996): H476—H484. http://dx.doi.org/10.1152/ajpheart.1996.270.2.h476.
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We have used the intracellular pH-sensitive fluorescent dye 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF) to characterize the substrate and inhibitor specificity of monocarboxylate transport into isolated rat heart cells. Further evidence was obtained for the presence of two lactate carriers present in heart cells (Wang et al., Biochem. J. 290: 249-258, 1993) both distinct from the recently cloned monocarboxylate transporter isoform 1 (MCT-1) found in many other cell types. Only one isoform was potently inhibited by alpha-cyano-4-hydroxycinnamate [CHC; inhibitor constant (Ki) 190 microM] and the stilbene disulfonates 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (Ki 79 microM) and 4,4'-dinitrostilbene-2,2'-disulfonate (Ki of cis- and trans-isomers 38 and 171 microM, respectively; neither isomer inhibits MCT-1). The second carrier had a Ki of approximately 3 mM for CHC and 0.5-2 mM for the stilbene disulfonates. Thus, unlike in many other tissues, in rat heart cells these inhibitors are not effective at blocking lactate transport totally unless used at very high concentrations. Both carriers were inhibited by 3-isobutyl-1-methylxanthine (Ki 340 microM) and neither by 5-nitro-2-(3-phenylpropylamino)benzoate (a potent inhibitor of MCT-1). The overall Michaelis constant (Km) and maximum reaction rate (Vmax) for transport of a variety of substituted monocarboxylates (C2-C5) were determined, although it was not possible to elucidate the kinetic parameters of the two isoforms. Of physiological interest, the ketone bodies D-beta-hydroxybutyrate and acetoacetate had K(m) values of 10 and 5.4 mM, respectively. Vmax values were similar to those of L-lactate and pyruvate and indicate that transport could limit rates of utilization of ketone bodies. No stereoselectivity for L-over D-isomers of 2-chloro or 2-hydroxy acids was observed.
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Chidlow, Glyn, John P. M. Wood, Mark Graham, and Neville N. Osborne. "Expression of monocarboxylate transporters in rat ocular tissues." American Journal of Physiology-Cell Physiology 288, no. 2 (February 2005): C416—C428. http://dx.doi.org/10.1152/ajpcell.00037.2004.
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The aim of the present study was to determine the distribution of monocarboxylate transporter (MCT) subtypes 1-4 in the various structures of the rat eye by using a combination of conventional and real-time RT-PCR, immunoblotting, and immunohistochemistry. Retinal samples expressed mRNAs encoding all four MCTs. MCT1 immunoreactivity was observed in photoreceptor inner segments, Müller cells, retinal capillaries, and the two plexiform layers. MCT2 labeling was concentrated in the inner and outer plexiform layers. MCT4 immunolabeling was present only in the inner retina, particularly in putative Müller cells, and the plexiform layers. No MCT3 labeling could be observed. The retinal pigment epithelium (RPE)/choroid expressed high levels of MCT1 and MCT3 mRNAs but lower levels of MCT2 and MCT4 mRNAs. MCT1 was localized to the apical and MCT3 to the basal membrane of the RPE, whereas MCT2 staining was faint. Although MCT1-MCT4 mRNAs were all detectable in iris and ciliary body samples, only MCT1 and MCT2 proteins were expressed. These were present in the iris epithelium and the nonpigmented epithelium of the ciliary processes. MCT4 was localized to the smooth muscle lining of large vessels in the iris-ciliary body and choroid. In the cornea, MCT1 and MCT2 mRNAs and proteins were detectable in the epithelium and endothelium, whereas evidence was found for the presence of MCT4 and, to a lesser extent, MCT1 in the lens epithelium. The unique distribution of MCT subtypes in the eye is indicative of the pivotal role that these transporters play in the maintenance of ocular function.
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Visser, W. Edward, Edith C. H. Friesema, and Theo J. Visser. "Minireview: Thyroid Hormone Transporters: The Knowns and the Unknowns." Molecular Endocrinology 25, no. 1 (January 1, 2011): 1–14. http://dx.doi.org/10.1210/me.2010-0095.
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The effects of thyroid hormone (TH) on development and metabolism are exerted at the cellular level. Metabolism and action of TH take place intracellularly, which require transport of the hormone across the plasma membrane. This process is mediated by TH transporter proteins. Many TH transporters have been identified at the molecular level, although a few are classified as specific TH transporters, including monocarboxylate transporter (MCT)8, MCT10, and organic anion-transporting polypeptide 1C1. The importance of TH transporters for physiology has been illustrated dramatically by the causative role of MCT8 mutations in males with psychomotor retardation and abnormal serum TH concentrations. Although Mct8 knockout animals have provided insight in the mechanisms underlying parts of the endocrine phenotype, they lack obvious neurological abnormalities. Thus, the pathogenesis of the neurological abnormalities in males with MCT8 mutations is not fully understood. The prospects of identifying other transporters and transporter-based syndromes promise an exciting future in the TH transporter field.
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Groeneweg, Stefan, Ferdy S. van Geest, Robin P. Peeters, Heike Heuer, and W. Edward Visser. "Thyroid Hormone Transporters." Endocrine Reviews 41, no. 2 (November 22, 2019): 146–201. http://dx.doi.org/10.1210/endrev/bnz008.
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Abstract Thyroid hormone transporters at the plasma membrane govern intracellular bioavailability of thyroid hormone. Monocarboxylate transporter (MCT) 8 and MCT10, organic anion transporting polypeptide (OATP) 1C1, and SLC17A4 are currently known as transporters displaying the highest specificity toward thyroid hormones. Structure-function studies using homology modeling and mutational screens have led to better understanding of the molecular basis of thyroid hormone transport. Mutations in MCT8 and in OATP1C1 have been associated with clinical disorders. Different animal models have provided insight into the functional role of thyroid hormone transporters, in particular MCT8. Different treatment strategies for MCT8 deficiency have been explored, of which thyroid hormone analogue therapy is currently applied in patients. Future studies may reveal the identity of as-yet-undiscovered thyroid hormone transporters. Complementary studies employing animal and human models will provide further insight into the role of transporters in health and disease.
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PRICE, T. Nigel, N. Vicky JACKSON, and P. Andrew HALESTRAP. "Cloning and sequencing of four new mammalian monocarboxylate transporter (MCT) homologues confirms the existence of a transporter family with an ancient past." Biochemical Journal 329, no. 2 (January 15, 1998): 321–28. http://dx.doi.org/10.1042/bj3290321.
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Measurement of monocarboxylate transport kinetics in a range of cell types has provided strong circumstantial evidence for a family of monocarboxylate transporters (MCTs). Two mammalian MCT isoforms (MCT1 and MCT2) and a chicken isoform (REMP or MCT3) have already been cloned, sequenced and expressed, and another MCT-like sequence (XPCT) has been identified. Here we report the identification of new human MCT homologues in the database of expression sequence tags and the cloning and sequencing of four new full-length MCT-like sequences from human cDNA libraries, which we have denoted MCT3, MCT4, MCT5 and MCT6. Northern blotting revealed a unique tissue distribution for the expression of mRNA for each of the seven putative MCT isoforms (MCT1-MCT6 and XPCT). All sequences were predicted to have 12 transmembrane (TM) helical domains with a large intracellular loop between TM6 and TM7. Multiple sequence alignments showed identities ranging from 20% to 55%, with the greatest conservation in the predicted TM regions and more variation in the C-terminal than the N-terminal region. Searching of additional sequence databases identified candidate MCT homologues from the yeast Saccharomyces cerevisiae, the nematode worm Caenorhabditis elegans and the archaebacterium Sulfolobus solfataricus. Together these sequences constitute a new family of transporters with some strongly conserved sequence motifs, the possible functions of which are discussed.
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Omlin, Teye, and Jean-Michel Weber. "Exhausting exercise and tissue-specific expression of monocarboxylate transporters in rainbow trout." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 304, no. 11 (June 1, 2013): R1036—R1043. http://dx.doi.org/10.1152/ajpregu.00516.2012.
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Transmembrane lactate movements are mediated by monocarboxylate transporters (MCTs), but these proteins have never been characterized in rainbow trout. Our goals were to clone potential trout MCTs, determine tissue distribution, and quantify the effects of exhausting exercise on MCT expression. Such information could prove important to understand the mechanisms underlying the classic “lactate retention ” seen in trout white muscle after intense exercise. Four isoforms were identified and partially characterized in rainbow trout: MCT1a, MCT1b, MCT2, and MCT4. MCT1b was the most abundant in heart and red muscle but poorly expressed in the gill and brain where MCT1a and MCT2 were prevalent. MCT expression was strongly stimulated by exhausting exercise in brain (MCT2: +260%) and heart (MCT1a: +90% and MCT1b: +50%), possibly to increase capacity for lactate uptake in these highly oxidative tissues. By contrast, the MCTs of gill, liver, and muscle remained unaffected by exercise. This study provides a possible functional explanation for postexercise “lactate retention” in trout white muscle. Rainbow trout may be unable to release large lactate loads rapidly during recovery because: 1) they only poorly express MCT4, the main lactate exporter found in mammalian glycolytic muscles; 2) the combined expression of all trout MCTs is much lower in white muscle than in any other tissue; and 3) exhausting exercise fails to upregulate white muscle MCT expression. In this tissue, carbohydrates act as an “energy spring” that alternates between explosive power release during intense swimming (glycogen to lactate) and recoil during protracted recovery (slow glycogen resynthesis from local lactate).
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Bader, Annika, and Eric Beitz. "Transmembrane Facilitation of Lactate/H+ Instead of Lactic Acid Is Not a Question of Semantics but of Cell Viability." Membranes 10, no. 9 (September 15, 2020): 236. http://dx.doi.org/10.3390/membranes10090236.
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Transmembrane transport of monocarboxylates is conferred by structurally diverse membrane proteins. Here, we describe the pH dependence of lactic acid/lactate facilitation of an aquaporin (AQP9), a monocarboxylate transporter (MCT1, SLC16A1), and a formate–nitrite transporter (plasmodium falciparum FNT, PfFNT) in the equilibrium transport state. FNTs exhibit a channel-like structure mimicking the aquaporin-fold, yet act as secondary active transporters. We used radiolabeled lactate to monitor uptake via yeast-expressed AQP9, MCT1, and PfFNT for long enough time periods to reach the equilibrium state in which import and export rates are balanced. We confirmed that AQP9 behaved perfectly equilibrative for lactic acid, i.e., the neutral lactic acid molecule enters and passes the channel. MCT1, in turn, actively used the transmembrane proton gradient and acted as a lactate/H+ co-transporter. PfFNT behaved highly similar to the MCT in terms of transport properties, although it does not adhere to the classical alternating access transporter model. Instead, the FNT appears to use the proton gradient to neutralize the lactate anion in the protein’s vestibule to generate lactic acid in a place that traverses the central hydrophobic transport path. In conclusion, we propose to include FNT-type proteins into a more generalized, function-based transporter definition.
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Jansen, S., M. Pantaleon, and P. Kaye. "236.Differential expression of monocarboxylate cotransporter proteins in preimplantation embryos." Reproduction, Fertility and Development 16, no. 9 (2004): 236. http://dx.doi.org/10.1071/srb04abs236.
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During preimplantation development mouse embryos demonstrate a switch in substrate preference. Pyruvate consumption, high during the first few cleavage stages, declines as the morula develops to a blastocyst, when glucose becomes the preferred substrate. Whilst pyruvate utilisation has been well characterised, changes in the function and expression of pyruvate transporters during this crucial period remain unclear. Pyruvate, lactate and other monocarboxylates are transported across mammalian cell membranes via a specific H+-monocarboxylate cotransporter (MCT). Fourteen members of this family have been identified of which MCT1, MCT2 and MCT4 are well characterised. Although mRNA expression profiles are known during early mouse development (1,2), the specific roles of each protein isoform are unknown. In order to understand these, the expression pattern for each isoform and their cellular localisation during preimplantation development have been determined. Mouse embryos were freshly collected from superovulated Quackenbush mice at 24, 48, 72 and 96 h post-hCG and expression of MCT1, MCT2 and MCT4 analysed by confocal laser scanning immunohistochemistry. Our results confirm that all three MCT proteins are expressed in preimplantation embryos. Immunoreactivity for MCT1 and MCT2 appears diffuse throughout the cytoplasm of cleavage stage embryos. As development proceeds, MCT1 localised to the basolateral membranes of morulae and blastocysts, whilst stronger MCT2 expression was found on the apical trophectoderm as well as the inner cell mass. MCT4 immunoreactivity on the other hand is apparent at cell-cell contact sites in cleavage stage embryos and morulae, but it is not apparent in the blastocyst. The demonstration of different expression patterns for MCT1, MCT2 and MCT4 in mouse embryos implies specific functional roles for each in the critical regulation of H+, pyruvate and lactate transport during preimplantation development. (1) Harding EA, Day ML, Gibb CA, Johnson MH, Cook DI (1999) The activity of the H+-monocarboxylate cotransporter during pre-implantation development in the mouse. Eur. J. Physiol. 438, 397–404. (2) H�rubel F, El Mouatassim S, Gu�rin P, Frydman R, M�n�zo Y (2002) Genetic expression of monocarboxylate transporters during human and murine oocyte maturation and early embryonic development. Zygote 10, 175–181.
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Yum, Jung-Joo, and Jun-Hee Yeon. "Lactate Dehydrogenase and Monocarboxylate Transporters 1, 2, and 4 in Tissues of Micropterus salmoides." Journal of Life Science 22, no. 1 (January 30, 2012): 98–109. http://dx.doi.org/10.5352/jls.2012.22.1.98.
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Kaji, Izumi, Toshihiko Iwanaga, Masahiko Watanabe, Paul H. Guth, Eli Engel, Jonathan D. Kaunitz, and Yasutada Akiba. "SCFA transport in rat duodenum." American Journal of Physiology-Gastrointestinal and Liver Physiology 308, no. 3 (February 1, 2015): G188—G197. http://dx.doi.org/10.1152/ajpgi.00298.2014.
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Bacterial or ingested food-derived short-chain fatty acids (SCFAs) are present in the duodenal lumen. Acetate, the most abundant SCFA in the foregut lumen, is absorbed immediately after ingestion, although the mechanism by which this absorption occurs is not fully understood. We investigated the distribution and function of candidate SCFA transporters in rat duodenum. The Na+-coupled monocarboxylate transporter-1 (SMCT1) was localized to the brush border, whereas the pH-dependent monocarboxylate transporter (MCT) 1 and MCT4 were localized to the duodenocyte basolateral membrane. In Ussing chambered duodenal mucosa, luminal acetate dose-dependently increased short-circuit current ( Isc) in the presence of serosal bumetanide and indomethacin by a luminal Na+-dependent, ouabain-sensitive mechanism. The Isc response was inhibited dose-dependently by the SMCT1 nonsubstrate inhibitor ibuprofen, consistent with net electrogenic absorption of acetate via SMCT1. Other SCFAs and lactate also increased Isc. Furthermore, duodenal loop perfusion of acetate increased portal venous acetate concentration, inhibited by coperfusion of ibuprofen or a MCT inhibitor. Luminal acetate perfusion increased duodenal HCO3− secretion via capsaicin-sensitive afferent nerve activation and cyclooxygenase activity, consistent with absorption-mediated HCO3− secretion. These results suggest that absorption of luminal SCFA via SMCT1 and MCTs increases duodenal HCO3− secretion. In addition to SCFA sensing via free fatty acid receptors, the presence of rapid duodenal SCFA absorption may be important for the suppression of luminal bacterial colonization and implicated in the generation of functional dyspepsia due to bacterial overgrowth.
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Koehler-Stec, E. M., I. A. Simpson, S. J. Vannucci, K. T. Landschulz, and W. H. Landschulz. "Monocarboxylate transporter expression in mouse brain." American Journal of Physiology-Endocrinology and Metabolism 275, no. 3 (September 1, 1998): E516—E524. http://dx.doi.org/10.1152/ajpendo.1998.275.3.e516.
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Although glucose is the major metabolic fuel needed for normal brain function, monocarboxylic acids, i.e., lactate, pyruvate, and ketone bodies, can also be utilized by the brain as alternative energy substrates. In most mammalian cells, these substrates are transported either into or out of the cell by a family of monocarboxylate transporters (MCTs), first cloned and sequenced in the hamster. We have recently cloned two MCT isoforms (MCT1 and MCT2) from a mouse kidney cDNA library. Northern blot analysis revealed that MCT1 mRNA is ubiquitous and can be detected in most tissues at a relatively constant level. MCT2 expression is more limited, with high levels of expression confined to testes, kidney, stomach, and liver and lower levels in lung, brain, and epididymal fat. Both MCT1 mRNA and MCT2 mRNA are detected in mouse brain using antisense riboprobes and in situ hybridization. MCT1 mRNA is found throughout the cortex, with higher levels of hybridization in hippocampus and cerebellum. MCT2 mRNA was detected in the same areas, but the pattern of expression was more specific. In addition, MCT1 mRNA, but not MCT2, is localized to the choroid plexus, ependyma, microvessels, and white matter structures such as the corpus callosum. These results suggest a differential expression of the two MCTs at the cellular level.
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Ng, Michael, Justin Louie, Jieyun Cao, and Melanie A. Felmlee. "Developmental Expression of Monocarboxylate Transporter 1 and 4 in Rat Liver." Journal of Pharmacy & Pharmaceutical Sciences 22 (July 30, 2019): 376–87. http://dx.doi.org/10.18433/jpps30537.
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Purpose: Monocarboxylate transporters (MCT) are proton-coupled integral membrane proteins that control the influx and efflux of endogenous monocarboxylates such as lactate, acetate and pyruvate. They also transport and mediate the clearance of drugs such as valproate and gamma-hydroxybutyrate. CD147 functions as ancillary protein that chaperones MCT1 and MCT4 to the cell membrane. There is limited data on the maturation of MCT and CD147 expression in tissues related to drug distribution and clearance. The objective of the present study was to quantify hepatic MCT1, MCT4, and CD147 mRNA, whole cell and membrane protein expression from birth to sexual maturity. Methods: Liver tissues were collected from male and female Sprague Dawley rats at postnatal days (PND) 1, 3, 5, 7, 10, 14, 18, 21, 28, 35, and 42 (n = 3 - 5). Hepatic mRNA, total and membrane protein expression of MCT1, MCT4, and CD147 was evaluated via qPCR and western blot. Results: MCT1 mRNA and protein demonstrated nonlinear maturation patterns. MCT1 and CD147 membrane protein exhibited low expression at birth, with expression increasing three-fold by PND14, followed by a decline in expression at sexual maturity. MCT4 mRNA had highest expression at PND 1, with decreasing expression towards sexual maturity. In contrast, MCT4 membrane protein exhibited minimal expression from birth through weaning before a 10-fold surge at PND35, whereupon there was a sharp decline in expression at PND42. There was a significant positive correlation between MCT1 and CD147 whole cell and membrane expression, while MCT4 membrane expression demonstrated a weak negative correlation with CD147. Conclusion: Our study elucidates the transcriptional and translational maturation patterns of MCT1, MCT4 and CD147 expression, with isoform-dependent differences in the liver. Changes in transporter expression during development may greatly influence drug distribution and clearance in pediatric populations.
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Friesema, Edith C. H., Jurgen Jansen, Jan-willem Jachtenberg, W. Edward Visser, Monique H. A. Kester, and Theo J. Visser. "Effective Cellular Uptake and Efflux of Thyroid Hormone by Human Monocarboxylate Transporter 10." Molecular Endocrinology 22, no. 6 (June 1, 2008): 1357–69. http://dx.doi.org/10.1210/me.2007-0112.
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Abstract Cellular entry of thyroid hormone is mediated by plasma membrane transporters, among others a T-type (aromatic) amino acid transporter. Monocarboxylate transporter 10 (MCT10) has been reported to transport aromatic amino acids but not iodothyronines. Within the MCT family, MCT10 is most homologous to MCT8, which is a very important iodothyronine transporter but does not transport amino acids. In view of this paradox, we decided to reinvestigate the possible transport of thyroid hormone by human (h) MCT10 in comparison with hMCT8. Transfection of COS1 cells with hMCT10 cDNA resulted in 1) the production of an approximately 55 kDa protein located to the plasma membrane as shown by immunoblotting and confocal microscopy, 2) a strong increase in the affinity labeling of intracellular type I deiodinase by N-bromoacetyl-[125I]T3, 3) a marked stimulation of cellular T4 and, particularly, T3 uptake, 4) a significant inhibition of T3 uptake by phenylalanine, tyrosine, and tryptophan of 12.5%, 22.2%, and 51.4%, respectively, and 5) a marked increase in the intracellular deiodination of T4 and T3 by different deiodinases. Cotransfection studies using the cytosolic thyroid hormone-binding protein μ-crystallin (CRYM) indicated that hMCT10 facilitates both cellular uptake and efflux of T4 and T3. In the absence of CRYM, hMCT10 and hMCT8 increased T3 uptake after 5 min incubation up to 4.0- and 1.9-fold, and in the presence of CRYM up to 6.9- and 5.8-fold, respectively. hMCT10 was less active toward T4 than hMCT8. These findings establish that hMCT10 is at least as active a thyroid hormone transporter as hMCT8, and that both transporters facilitate iodothyronine uptake as well as efflux.
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Gill, Ravinder K., Seema Saksena, Waddah A. Alrefai, Zaheer Sarwar, Jay L. Goldstein, Robert E. Carroll, Krishnamurthy Ramaswamy, and Pradeep K. Dudeja. "Expression and membrane localization of MCT isoforms along the length of the human intestine." American Journal of Physiology-Cell Physiology 289, no. 4 (October 2005): C846—C852. http://dx.doi.org/10.1152/ajpcell.00112.2005.
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Recent studies from our laboratory and others have demonstrated the involvement of monocarboxylate transporter (MCT)1 in the luminal uptake of short-chain fatty acids (SCFAs) in the human intestine. Functional studies from our laboratory previously demonstrated kinetically distinct SCFA transporters on the apical and basolateral membranes of human colonocytes. Although apical SCFA uptake is mediated by the MCT1 isoform, the molecular identity of the basolateral membrane SCFA transporter(s) and whether this transporter is encoded by another MCT isoform is not known. The present studies were designed to assess the expression and membrane localization of different MCT isoforms in human small intestine and colon. Immunoblotting was performed with the purified apical and basolateral membranes from human intestinal mucosa obtained from organ donor intestine. Immunohistochemistry studies were done on paraffin-embedded sections of human colonic biopsy samples. Immunoblotting studies detected a protein band of ∼39 kDa for MCT1, predominantly in the apical membranes. The relative abundance of MCT1 mRNA and protein increased along the length of the human intestine. MCT4 (54 kDa) and MCT5 (54 kDa) isoforms showed basolateral localization and were highly expressed in the distal colon. Immunohistochemical studies confirmed that human MCT1 antibody labeling was confined to the apical membranes, whereas MCT5 antibody staining was restricted to the basolateral membranes of the colonocytes. We speculate that distinct MCT isoforms may be involved in SCFA transport across the apical or basolateral membranes in polarized colonic epithelial cells.
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KOHO, N. M., S. HYYPPÄ, and A. R. PÖSÖ. "Monocarboxylate transporters (MCT) as lactate carriers in equine muscle and red blood cells." Equine Veterinary Journal 38, S36 (August 2006): 354–58. http://dx.doi.org/10.1111/j.2042-3306.2006.tb05568.x.
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McClelland, Grant B., and George A. Brooks. "Changes in MCT 1, MCT 4, and LDH expression are tissue specific in rats after long-term hypobaric hypoxia." Journal of Applied Physiology 92, no. 4 (April 1, 2002): 1573–84. http://dx.doi.org/10.1152/japplphysiol.01069.2001.
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Little is known about the effect of chronic hypobaric hypoxia on the enzymes and transporters involved in lactate metabolism. We looked at the protein expression of monocarboxylate transporters MCT 1, MCT 2, and MCT 4, along with total lactate dehydrogenase (LDH) and LDH isozymes in skeletal muscle, cardiac muscle, and liver. Expression of these components of the lactate shuttle affects the ability to transport and oxidize lactate. We hypothesized that the expression of MCTs and LDH would increase after acclimation to high altitude (HA). The response to acclimation to HA was, however, tissue specific. In addition, the response was different in whole muscle (Mu) and mitochondria-enriched (Mi) fractions. Heart, soleus, and plantaris muscles showed the greatest response to HA. Acclimation resulted in a 34% increase in MCT 4 in heart and a decrease in MCT 1 (−47%) and MCT 4 (−47%) in plantaris Mu. In Mi fractions, the heart had an increase (+40%) and soleus a decrease (−40%) in LDH. HA also had a significant effect on the LDH isozyme composition of both the Mu and Mi fractions. Mitochondrial density was decreased in both the soleus (−17%) and plantaris (−44%) as a result of chronic hypoxia. We conclude that chronic hypoxia had a tissue-specific effect on MCTs and LDH (that form the lactate shuttle) but did not produce a consistent increase in these components in all tissues.
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HALESTRAP, Andrew P., and Nigel T. PRICE. "The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation." Biochemical Journal 343, no. 2 (October 8, 1999): 281–99. http://dx.doi.org/10.1042/bj3430281.
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Monocarboxylates such as lactate and pyruvate play a central role in cellular metabolism and metabolic communication between tissues. Essential to these roles is their rapid transport across the plasma membrane, which is catalysed by a recently identified family of proton-linked monocarboxylate transporters(MCTs). Nine MCT-related sequences have so far been identified in mammals, each having a different tissue distribution, whereas six related proteins can be recognized in Caenorhabditis elegansand 4 in Saccharomyces cerevisiae. Direct demonstration of proton-linked lactate and pyruvate transport has been demonstrated for mammalian MCT1-MCT4, but only for MCT1 and MCT2 have detailed analyses of substrate and inhibitor kinetics been described following heterologous expression in Xenopusoocytes. MCT1 is ubiquitously expressed, but is especially prominent in heart and red muscle, where it is up-regulated in response to increased work, suggesting a special role in lactic acid oxidation. By contrast, MCT4 is most evident in white muscle and other cells with a high glycolytic rate, such as tumour cells and white blood cells, suggesting it is expressed where lactic acid efflux predominates. MCT2 has a ten-fold higher affinity for substrates than MCT1 and MCT4 and is found in cells where rapid uptake at low substrate concentrations may be required, including the proximal kidney tubules, neurons and sperm tails. MCT3 is uniquely expressed in the retinal pigment epithelium. The mechanisms involved in regulating the expression of different MCT isoforms remain to be established. However, there is evidence for alternative splicing of the 5′- and 3′-untranslated regions and the use of alternative promoters for some isoforms. In addition, MCT1 and MCT4 have been shown to interact specifically with OX-47 (CD147), a member of the immunoglobulin superfamily with a single transmembrane helix. This interaction appears to assist MCT expression at the cell surface. There is still much work to be done to characterize the properties of the different isoforms and their regulation, which may have wide-ranging implications for health and disease. In the future it will be interesting to explore the linkage of genetic diseases to particular MCTs through their chromosomal location.
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Cao, Jieyun, Michael Ng, and Melanie A. Felmlee. "Sex Hormones Regulate Rat Hepatic Monocarboxylate Transporter Expression and Membrane Trafficking." Journal of Pharmacy & Pharmaceutical Sciences 20, no. 1 (December 15, 2017): 435. http://dx.doi.org/10.18433/j3ch29.
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Purpose: Monocarboxylate transporters (MCTs) are involved in the transport of monocarboxylates such as ketone bodies, lactate, and pharmaceutical agents. CD147 functions as an ancillary protein for MCT1 and MCT4 for plasma membrane trafficking. Sex differences in MCT1 and MCT4 have been observed in muscle and reproductive tissues; however, there is a paucity of information on MCT sex differences in tissues involved in drug disposition. The objective of the present study was to quantify hepatic MCT1, MCT4 and CD147 mRNA, total cellular and membrane protein expression in males, over the estrous cycle in females and in ovariectomized (OVX) females. Method: Liver samples were collected from females at the four estrous cycle stages (proestrus, estrus, metestrus, diestrus), OVX females and male Sprague-Dawley rats (N = 3 – 5). Estrus cycle stage of females was determined by vaginal lavage. mRNA and protein (total and membrane) expression of MCT1, MCT4 and CD147 was evaluated by qPCR and western blot analysis. Results: MCT1 mRNA and membrane protein expression varied with estrous cycle stage, with OVX females having higher expression than males, indicating that female sex hormones may play a role in MCT1 regulation. MCT4 membrane expression varied with estrous cycle stage with expression significantly lower than males. MCT4 membrane expression in OVX females was also lower than males, suggesting that androgens play a role in membrane expression of MCT4. Males had higher membrane CD147 expression, whereas there was no difference in whole cell protein and mRNA levels suggesting that androgens are involved in regulating CD147 membrane localization. Conclusions: This study demonstrates hepatic expression and membrane localization of MCT1, MCT4 and CD147 are regulated by sex hormones. Sex differences in hepatic MCT expression may lead to altered drug disposition, so it is critical to elucidate the underlying mechanisms in the sex hormone-dependent regulation of MCT expression. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.
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Bonen, Arend, Miriam Heynen, and Hideo Hatta. "Distribution of monocarboxylate transporters MCT1-MCT8 in rat tissues and human skeletal muscle." Applied Physiology, Nutrition, and Metabolism 31, no. 1 (February 1, 2006): 31–39. http://dx.doi.org/10.1139/h05-002.
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In the past decade, a family of monocarboxylate transporters (MCTs) have been identified that can potentially transport lactate, pyruvate, ketone bodies, and branched-chain ketoacids. Currently, 14 such MCTs are known. However, many orphan transporters exist that have transport capacities that remain to be determined. In addition, the tissue distribution of many of these MCTs is not well defined. Such a cataloging can, at times, begin to suggest the metabolic role of a particular MCT. Recently, a number of antibodies against selected MCTs (MCT1, -2, -4, and -5 to -8) have become commercially available. Therefore, we examined the protein expression of these MCTs in a large number of rat tissues (heart, skeletal muscle, skin, brain, testes, vas deferens, adipose tissue, liver, kidney, spleen, and pancreas), as well as in human skeletal muscle. Unexpectedly, many tissues coexpressed 4-5 MCTs. In particular, in rat skeletal muscle MCT1, MCT2, MCT4, MCT5, and MCT6 were observed. In human muscle, these same MCTs were present. We also observed a pronounced MCT7 signal in human muscle, whereas a very faint signal occurred for MCT8. In rat heart, which is an important metabolic sink for lactate, we confirmed that MCT1 and -2 were expressed. In addition, MCT6 and -8 were also prominently expressed in this tissue, although it is known that MCT8 does not transport aromatic amino acids or lactate. This catalog of MCTs in skeletal muscle and other tissues has revealed an unexpected complexity of coexpression, which makes it difficult to associate changes in monocarboxylate transport with the expression of a particular MCT. The differences in transport kinetics for lactate and pyruvate are only known for MCT1, -2 and -4. Transport kinetics remain to be established for many other MCTs. In conclusion, this study suggests that in skeletal muscle, as well as other tissues, lactate and pyruvate transport rates may not only involve MCT1 and -4, as other monocarboxylate transporters are also expressed in rat (MCT2, -5, -6) and human skeletal muscle (MCT2, -5, -6, -7).Key words: muscle, lactate, pyruvate, human, rat.
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Pinheiro, Céline, Rui M. Reis, Sara Ricardo, Adhemar Longatto-Filho, Fernando Schmitt, and Fátima Baltazar. "Expression of Monocarboxylate Transporters 1, 2, and 4 in Human Tumours and Their Association with CD147 and CD44." Journal of Biomedicine and Biotechnology 2010 (2010): 1–7. http://dx.doi.org/10.1155/2010/427694.
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Monocarboxylate transporters (MCTs) are important cellular pH regulators in cancer cells; however, the value of MCT expression in cancer is still poorly understood. In the present study, we analysed MCT1, MCT2, and MCT4 protein expression in breast, colon, lung, and ovary neoplasms, as well as CD147 and CD44. MCT expression frequency was high and heterogeneous among the different tumours. Comparing with normal tissues, there was an increase in MCT1 and MCT4 expressions in breast carcinoma and a decrease in MCT4 plasma membrane expression in lung cancer. There were associations between CD147 and MCT1 expressions in ovarian cancer as well as between CD147 and MCT4 in both breast and lung cancers. CD44 was only associated with MCT1 plasma membrane expression in lung cancer. An important number of MCT1 positive cases are negative for both chaperones, suggesting that MCT plasma membrane expression in tumours may depend on a yet nonidentified regulatory protein.
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Gallagher, Shannon M., John J. Castorino, and Nancy J. Philp. "Interaction of monocarboxylate transporter 4 with β1-integrin and its role in cell migration." American Journal of Physiology-Cell Physiology 296, no. 3 (March 2009): C414—C421. http://dx.doi.org/10.1152/ajpcell.00430.2008.
Full textAbstract:
Monocarboxylate transporter (MCT) 4 is a heteromeric proton-coupled lactate transporter that is noncovalently linked to the extracellular matrix metalloproteinase inducer CD147 and is typically expressed in glycolytic tissues. There is increasing evidence to suggest that ion transporters are part of macromolecular complexes involved in regulating β1-integrin adhesion and cell movement. In the present study we examined whether MCTs play a role in cell migration through their interaction with β1-integrin. Using reciprocal coimmunoprecipitation assays, we found that β1-integrin selectively associated with MCT4 in ARPE-19 and MDCK cells, two epithelial cell lines that express both MCT1 and MCT4. In polarized monolayers of ARPE-19 cells, MCT4 and β1-integrin colocalized to the basolateral membrane, while both proteins were found in the leading edge lamellapodia of migrating cells. In scratch-wound assays, MCT4 knockdown slowed migration and increased focal adhesion size. In contrast, silencing MCT1 did not alter the rate of cell migration or focal adhesion size. Taken together, our findings suggest that the specific interaction of MCT4 with β1-integrin may regulate cell migration through modulation of focal adhesions.
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Ward, Carol, James Meehan, Mark E. Gray, Alan F. Murray, David J. Argyle, Ian H. Kunkler, and Simon P. Langdon. "The impact of tumour pH on cancer progression: strategies for clinical intervention." Exploration of Targeted Anti-tumor Therapy 1, no. 2 (April 9, 2020): 71–100. http://dx.doi.org/10.37349/etat.2020.00005.
Full textAbstract:
Dysregulation of cellular pH is frequent in solid tumours and provides potential opportunities for therapeutic intervention. The acidic microenvironment within a tumour can promote migration, invasion and metastasis of cancer cells through a variety of mechanisms. Pathways associated with the control of intracellular pH that are under consideration for intervention include carbonic anhydrase IX, the monocarboxylate transporters (MCT, MCT1 and MCT4), the vacuolar-type H+-ATPase proton pump, and the sodium-hydrogen exchanger 1. This review will describe progress in the development of inhibitors to these targets.
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Green, H. J., T. A. Duhamel, G. P. Holloway, J. W. Moule, D. W. Ranney, A. R. Tupling, and J. Ouyang. "Rapid upregulation of GLUT-4 and MCT-4 expression during 16 h of heavy intermittent cycle exercise." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 294, no. 2 (February 2008): R594—R600. http://dx.doi.org/10.1152/ajpregu.00699.2007.
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In this study, we have investigated the hypothesis that an exercise protocol designed to repeatedly induce a large dependence on carbohydrate and large increases in glycolytic flux rate would result in rapid increases in the principal glucose and lactate transporters in working muscle, glucose transporter (GLUT)-4 and monocarboxylate transporter (MCT)4, respectively, and in activity of hexokinase (Hex), the enzyme used to phosphorylate glucose. Transporter abundance and Hex activity were assessed in homogenates by Western blotting and quantitative chemiluminescence and fluorometric techniques, respectively, in samples of tissue obtained from the vastus lateralis in 12 untrained volunteers [peak aerobic power (V̇o2peak) = 44.3 ± 2.3 ml·kg−1·min−1] before cycle exercise at repetitions 1 (R1), 2 (R2), 9 (R9), and 16 (R16). The 16 repetitions of the exercise were performed for 6 min at ∼90% V̇o2peak, once per hour. Compared with R1, GLUT-4 increased ( P < 0.05) by 28% at R2 and remained elevated ( P < 0.05) at R9 and R16. For MCT-4, increases ( P < 0.05) of 24% were first observed at R9 and persisted at R16. No changes were observed in GLUT-1 and MCT-1 or in Hex activity. The ∼17- to 24-fold increase ( P < 0.05) in muscle lactate observed at R1 and R2 was reduced ( P < 0.05) to an 11-fold increase at R9 and R16. It is concluded that an exercise protocol designed to strain muscle carbohydrate reserves and to result in large increases in lactic acid results in a rapid upregulation of both GLUT-4 and MCT-4.
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Väihkönen, Leena K., and A. Reeta Pösö. "Interindividual variation in total and carrier-mediated lactate influx into red blood cells." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 274, no. 4 (April 1, 1998): R1025—R1030. http://dx.doi.org/10.1152/ajpregu.1998.274.4.r1025.
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To study in standardbred horses interindividual variation in the influx of lactate into red blood cells, venous blood samples were collected from 89 horses from 2 wk to 9 yr of age. For 62 horses, the rate of influx was normally distributed with a mean rate of 4.09 nmol ⋅ mg protein−1 ⋅ min−1at a lactate concentration of 10 mM, and the respective value for the other 27 horses was 0.58 nmol ⋅ mg protein−1 ⋅ min−1. At 30 mM of lactate, the rates were 8.71 and 1.97 nmol ⋅ mg protein−1 ⋅ min−1, respectively. This bimodal distribution was independent of age. In horses with high transport activity, the monocarboxylate transporter (MCT) appears to be the major carrier, whereas, in those with low transport activity, no activity of the MCT could be detected. The band 3 protein may account for 18–39% of transport activity. With all age groups combined, the transport activity tended to be higher in mares than in stallions. Lactate transport into red blood cells seems thus to be an inherent property in which participation of various transporters varies interindividually.
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Yoshida, Go J. "The Harmonious Interplay of Amino Acid and Monocarboxylate Transporters Induces the Robustness of Cancer Cells." Metabolites 11, no. 1 (January 2, 2021): 27. http://dx.doi.org/10.3390/metabo11010027.
Full textAbstract:
There is a growing body of evidence that metabolic reprogramming contributes to the acquisition and maintenance of robustness associated with malignancy. The fine regulation of expression levels of amino acid and monocarboxylate transporters enables cancer cells to exhibit the metabolic reprogramming that is responsible for therapeutic resistance. Amino acid transporters characterized by xCT (SLC7A11), ASCT2 (SLC1A5), and LAT1 (SLC7A5) function in the uptake and export of amino acids such as cystine and glutamine, thereby regulating glutathione synthesis, autophagy, and glutaminolysis. CD44 variant, a cancer stem-like cell marker, stabilizes the xCT antiporter at the cellular membrane, and tumor cells positive for xCT and/or ASCT2 are susceptible to sulfasalazine, a system Xc(-) inhibitor. Inhibiting the interaction between LAT1 and CD98 heavy chain prevents activation of the mammalian target of rapamycin (mTOR) complex 1 by glutamine and leucine. mTOR signaling regulated by LAT1 is a sensor of dynamic alterations in the nutrient tumor microenvironment. LAT1 is overexpressed in various malignancies and positively correlated with poor clinical outcome. Metabolic reprogramming of glutamine occurs often in cancer cells and manifests as ASCT2-mediated glutamine addiction. Monocarboxylate transporters (MCTs) mediate metabolic symbiosis, by which lactate in cancer cells under hypoxia is exported through MCT4 and imported by MCT1 in less hypoxic regions, where it is used as an oxidative metabolite. Differential expression patterns of transporters cause functional intratumoral heterogeneity leading to the therapeutic resistance. Therefore, metabolic reprogramming based on these transporters may be a promising therapeutic target. This review highlights the pathological function and therapeutic targets of transporters including xCT, ASCT2, LAT1, and MCT.
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Hussien, Rajaa, and George A. Brooks. "Mitochondrial and plasma membrane lactate transporter and lactate dehydrogenase isoform expression in breast cancer cell lines." Physiological Genomics 43, no. 5 (March 2011): 255–64. http://dx.doi.org/10.1152/physiolgenomics.00177.2010.
Full textAbstract:
We hypothesized that dysregulation of lactate/pyruvate (monocarboxylate) transporters (MCT) and lactate dehydrogenase (LDH) isoforms contribute to the Warburg effect in cancer. Therefore, we assayed for the expression levels and the localizations of MCT ( 1 , 2 , and 4 ), and LDH (A and B) isoforms in breast cancer cell lines MCF-7 and MDA-MB-231 and compared results with those from a control, untransformed primary breast cell line, HMEC 184. Remarkably, MCT1 is not expressed in MDA-MB-231, but MCT1 is expressed in MCF-7 cells, where its abundance is less than in control HMEC 184 cells. When present in HMEC 184 and MCF-7 cells, MCT1 is localized to the plasma membrane. MCT2 and MCT4 were expressed in all the cell lines studied. MCT4 expression was higher in MDA-MB-231 compared with MCF-7 and HMEC 184 cells, whereas MCT2 abundance was higher in MCF-7 compared with MDA-MB-231 and HMEC 184 cells. Unlike MCT1, MCT2 and MCT4 were localized in mitochondria in addition to the plasma membrane. LDHA and LDHB were expressed in all the cell-lines, but abundances were higher in the two cancer cell lines than in the control cells. MCF-7 cells expressed mainly LDHB, while MDA-MB-231 and control cells expressed mainly LDHA. LDH isoforms were localized in mitochondria in addition to the cytosol. These localization patterns were the same in cancerous and control cell lines. In conclusion, MCT and LDH isoforms have distinct expression patterns in two breast cancer cell lines. These differences may contribute to divergent lactate dynamics and oxidative capacities in these cells, and offer possibilities for targeting cancer cells.
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Pinheiro, Céline, Adhemar Longatto-Filho, Sônia Maria Miranda Pereira, Daniela Etlinger, Marise A. R. Moreira, Luiz Fernando Jubé, Geraldo Silva Queiroz, Fernando Schmitt, and Fátima Baltazar. "Monocarboxylate Transporters 1 and 4 Are Associated with CD147 in Cervical Carcinoma." Disease Markers 26, no. 3 (2009): 97–103. http://dx.doi.org/10.1155/2009/169678.
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Due to the highly glycolytic metabolism of solid tumours, there is an increased acid production, however, cells are able to maintain physiological pH through plasma membrane efflux of the accumulating protons. Acid efflux through MCTs (monocarboxylate transporters) constitutes one of the most important mechanisms involved in tumour intracellular pH maintenance. Still, the molecular mechanisms underlying the regulation of these proteins are not fully understood. We aimed to evaluate the association between CD147 (MCT1 and MCT4 chaperone) and MCT expression in cervical cancer lesions and the clinico-pathological significance of CD147 expression, alone and in combination with MCTs. The series included 83 biopsy samples of precursor lesions and surgical specimens of 126 invasive carcinomas. Analysis of CD147 expression was performed by immunohistochemistry. CD147 expression was higher in squamous and adenocarcinoma tissues than in the non-neoplastic counterparts and, importantly, both MCT1 and MCT4 were more frequently expressed in CD147 positive cases. Additionally, co-expression of CD147 with MCT1 was associated with lymph-node and/or distant metastases in adenocarcinomas. Our results show a close association between CD147 and MCT1 and MCT4 expressions in human cervical cancer and provided evidence for a prognostic value of CD147 and MCT1 co-expression.
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Graham, C., I. Gatherar, I. Haslam, M. Glanville, and N. L. Simmons. "Expression and localization of monocarboxylate transporters and sodium/proton exchangers in bovine rumen epithelium." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 292, no. 2 (February 2007): R997—R1007. http://dx.doi.org/10.1152/ajpregu.00343.2006.
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Monocarboxylate-H+ cotransporters, such as monocarboxylate transporter (MCT) SLC16A, have been suggested to mediate transruminal fluxes of short-chain fatty acids, ketone bodies, and lactate. Using an RT-PCR approach, we demonstrate expression of MCT1 (SLC16A1) and MCT2 (SLC16A7) mRNA in isolated bovine rumen epithelium. cDNA sequence from these PCR products combined with overlapping expressed sequence tag data allowed compilation of the complete open reading frames for MCT1 and MCT2. Immunohistochemical localization of MCT1 shows plasma membrane staining in cells of the stratum basale, with intense staining of the basal aspects of the cells. Immunostaining decreased in the cell layers toward the rumen lumen, with weak staining in the stratum spinsoum. Immunostaining in the stratum granulosum and stratum corneum was essentially negative. Since monocarboxylate transport will load the cytosol with acid, expression and location of Na+/H+ exchanger (NHE) family members within the rumen epithelium were determined. RT-PCR demonstrates expression of multiple NHE family members, including NHE1, NHE2, NHE3, and NHE8. In contrast to MCT1, immunostaining showed that NHE1 was predominantly localized to the stratum granulosum, with a progressive decrease toward the stratum basale. NHE2 immunostaining was observed mainly at an intracellular location in the stratum basale, stratum spinosum, and stratum granulosum. Given the anatomic localization of MCT1, NHE1, and NHE2, the mechanism of transruminal short-chain fatty acid, ketone body, and lactate transfer is discussed in relation to a functional model of the rumen epithelium comprising an apical permeability barrier at the stratum granulosum, with a cell syncitium linking the stratum granulosum to the blood-facing stratum basale.
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Hérubel, François, Saïd El Mouatassim, Pierre Guérin, René Frydman, and Yves Ménézo. "Genetic expression of monocarboxylate transporters during human and murine oocyte maturation and early embryonic development." Zygote 10, no. 2 (May 2002): 175–81. http://dx.doi.org/10.1017/s096719940200223x.
Full textAbstract:
During the early preimplantation stages of human embryos, pyruvate and lactate, but not glucose, are the preferred energy substrates. Transport of these monocarboxylates is mediated, in mammalian cells, by a family of transporters, designated as monocarboxylate transporters (MCTs). Human and mouse genetic expression of MCT members 1, 2, 3, 4 and basigin, a chaperone protein of MCT1 and MCT4, was qualitatively analysed using the reverse transcription nested polymerase chain reaction (RT-nested PCR) in immature oocytes (germinal vesicle stage; GV), in non-fertilised metaphase II (MII) oocytes and in embryos from 2-cell stage to blastocysts. Transcripts encoding for MCT1 and MCT2 were present, under a polyadenylated form, in the majority of the human and mouse oocytes and early embryos. MCT3 transcripts were not detected in either human or mouse. MCT4 mRNA was not detected in human oocytes and embryos, but was present in mouse oocytes and embryos. This fact could imply differences in lactate transport and regulation of intracellular pH between human and murine early embryos. Basigin transcripts were present in mouse and human MII oocytes and preimplantation embryos, but were not detected at GV stage. However, using 3' end-specific primers in the RT reaction instead of Oligo(dT)12-18 primers, transcripts encoding for this protein were then detected at GV stage in both species. This result suggests that a regulated polyadenylation process occurs during oocyte maturation for these transcripts. Thus, basigin mRNA can be considered as a marker of oocyte cytoplasmic maturation in human and mouse species.
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Sharlin, David S., Theo J. Visser, and Douglas Forrest. "Developmental and Cell-Specific Expression of Thyroid Hormone Transporters in the Mouse Cochlea." Endocrinology 152, no. 12 (August 30, 2011): 5053–64. http://dx.doi.org/10.1210/en.2011-1372.
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Thyroid hormone is essential for the development of the cochlea and auditory function. Cochlear response tissues, which express thyroid hormone receptor β (encoded by Thrb), include the greater epithelial ridge and sensory epithelium residing inside the bony labyrinth. However, these response tissues lack direct blood flow, implying that mechanisms exist to shuttle hormone from the circulation to target tissues. Therefore, we investigated expression of candidate thyroid hormone transporters L-type amino acid transporter 1 (Lat1), monocarboxylate transporter (Mct)8, Mct10, and organic anion transporting polypeptide 1c1 (Oatp1c1) in mouse cochlear development by in situ hybridization and immunofluorescence analysis. L-type amino acid transporter 1 localized to cochlear blood vessels and transiently to sensory hair cells. Mct8 localized to the greater epithelial ridge, tympanic border cells underlying the sensory epithelium, spiral ligament fibrocytes, and spiral ganglion neurons, partly overlapping with the Thrb expression pattern. Mct10 was detected in a highly restricted pattern in the outer sulcus epithelium and weakly in tympanic border cells and hair cells. Organic anion transporting polypeptide 1c1 localized primarily to fibrocytes in vascularized tissues of the spiral limbus and spiral ligament and to tympanic border cells. Investigation of hypothyroid Tshr−/− mice showed that transporter expression was delayed consistent with retardation of cochlear tissue maturation but not with compensatory responses to hypothyroidism. The results demonstrate specific expression of thyroid hormone transporters in the cochlea and suggest that a network of thyroid hormone transport underlies cochlear development.
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Thomas, Claire, David J. Bishop, Karen Lambert, Jacques Mercier, and George A. Brooks. "Effects of acute and chronic exercise on sarcolemmal MCT1 and MCT4 contents in human skeletal muscles: current status." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 302, no. 1 (January 2012): R1—R14. http://dx.doi.org/10.1152/ajpregu.00250.2011.
Full textAbstract:
Two lactate/proton cotransporter isoforms (monocarboxylate transporters, MCT1 and MCT4) are present in the plasma (sarcolemmal) membranes of skeletal muscle. Both isoforms are symports and are involved in both muscle pH and lactate regulation. Accordingly, sarcolemmal MCT isoform expression may play an important role in exercise performance. Acute exercise alters human MCT content, within the first 24 h from the onset of exercise. The regulation of MCT protein expression is complex after acute exercise, since there is not a simple concordance between changes in mRNA abundance and protein levels. In general, exercise produces greater increases in MCT1 than in MCT4 content. Chronic exercise also affects MCT1 and MCT4 content, regardless of the initial fitness of subjects. On the basis of cross-sectional studies, intensity would appear to be the most important factor regulating exercise-induced changes in MCT content. Regulation of skeletal muscle MCT1 and MCT4 content by a variety of stimuli inducing an elevation of lactate level (exercise, hypoxia, nutrition, metabolic perturbations) has been demonstrated. Dissociation between the regulation of MCT content and lactate transport activity has been reported in a number of studies, and changes in MCT content are more common in response to contractile activity, whereas changes in lactate transport capacity typically occur in response to changes in metabolic pathways. Muscle MCT expression is involved in, but is not the sole determinant of, muscle H+and lactate anion exchange during physical activity.
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Diers, Anne R., Katarzyna A. Broniowska, Ching-Fang Chang, and Neil Hogg. "Pyruvate fuels mitochondrial respiration and proliferation of breast cancer cells: effect of monocarboxylate transporter inhibition." Biochemical Journal 444, no. 3 (May 29, 2012): 561–71. http://dx.doi.org/10.1042/bj20120294.
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Recent studies have highlighted the fact that cancer cells have an altered metabolic phenotype, and this metabolic reprogramming is required to drive the biosynthesis pathways necessary for rapid replication and proliferation. Specifically, the importance of citric acid cycle-generated intermediates in the regulation of cancer cell proliferation has been recently appreciated. One function of MCTs (monocarboxylate transporters) is to transport the citric acid cycle substrate pyruvate across the plasma membrane and into mitochondria, and inhibition of MCTs has been proposed as a therapeutic strategy to target metabolic pathways in cancer. In the present paper, we examined the effect of different metabolic substrates (glucose and pyruvate) on mitochondrial function and proliferation in breast cancer cells. We demonstrated that cancer cells proliferate more rapidly in the presence of exogenous pyruvate when compared with lactate. Pyruvate supplementation fuelled mitochondrial oxygen consumption and the reserve respiratory capacity, and this increase in mitochondrial function correlated with proliferative potential. In addition, inhibition of cellular pyruvate uptake using the MCT inhibitor α-cyano-4-hydroxycinnamic acid impaired mitochondrial respiration and decreased cell growth. These data demonstrate the importance of mitochondrial metabolism in proliferative responses and highlight a novel mechanism of action for MCT inhibitors through suppression of pyruvate-fuelled mitochondrial respiration.
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Huang, Hsu-Kai, Shin-Yi Lee, Shu-Fen Huang, Yu-San Lin, Shih-Chi Chao, Shu-Fu Huang, Shih-Chun Lee, Tzu-Hurng Cheng, Shih-Hurng Loh, and Yi-Ting Tsai. "Isoorientin Decreases Cell Migration via Decreasing Functional Activity and Molecular Expression of Proton-Linked Monocarboxylate Transporters in Human Lung Cancer Cells." American Journal of Chinese Medicine 48, no. 01 (January 2020): 201–22. http://dx.doi.org/10.1142/s0192415x20500111.
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Aggressive tumor cells mainly rely on glycolysis, and further release vast amounts of lactate and protons by monocarboxylate transporter (MCT), which causes a higher intracellular pH (pHi) and acidic extracellular pH. Isoorientin, a principle flavonoid compound extracted from several plant species, shows various pharmacological activities. However, effects of isoorientin on anticancer and MCT await to explore in human lung cancer cells. Human lung cancer tissues were obtained from cancer patients undergoing surgery, while the human lung adenocarcinoma cells (A549) were bought commercially. Change of pHi was detected by microspectrofluorometry method with a pH-sensitive fluorescent dye, BCECF. MTT and wound-healing assay were used to detect the cell viability and migration, respectively. Western blot techniques and immunocytochemistry staining were used to detect the protein expression. Our results indicated that the expression of MCTs1/4 and CD147 were upregulated significantly in human lung tissues. In experiments of A549 cells, under HEPES-buffer, the resting pHi was 7.47, and isoorientin (1–300[Formula: see text][Formula: see text]M) inhibited functional activity of MCT concentration-dependently (up to [Formula: see text]%). Pretreatment with isoorientin (3–100[Formula: see text][Formula: see text]M) for 24[Formula: see text]h, MCT activity and cell migration were significantly inhibited ([Formula: see text]% and [Formula: see text]%, respectively), while the cell viability was not affected. Moreover, the expression of MCTs1/4, CD147, and matrix metalloproteinase (MMP) 2/9 were significantly down regulated. In summary, MCTs1/4 and CD147 are significantly upregulated in human lung adenocarcinoma tissues, and isoorientin inhibits cells-migration by inhibiting activity/expression of MCTs1/4 and MMPs2/9 in human lung cancer cells. These novel findings suggest that isoorientin could be a promising pharmacological agent for lung cancer.
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Moreira, Tiago JTP, Karin Pierre, Fumihiko Maekawa, Cendrine Repond, Aleta Cebere, Sture Liljequist, and Luc Pellerin. "Enhanced Cerebral Expression of MCT1 and MCT2 in a Rat Ischemia Model Occurs in Activated Microglial Cells." Journal of Cerebral Blood Flow & Metabolism 29, no. 7 (April 29, 2009): 1273–83. http://dx.doi.org/10.1038/jcbfm.2009.50.
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Monocarboxylate transporters (MCTs) are essential for the use of lactate, an energy substrate known to be overproduced in brain during an ischemic episode. The expression of MCT1 and MCT2 was investigated at 48 h of reperfusion from focal ischemia induced by unilateral extradural compression in Wistar rats. Increased MCT1 mRNA expression was detected in the injured cortex and hippocampus of compressed animals compared to sham controls. In the contralateral, uncompressed hemisphere, increases in MCT1 mRNA level in the cortex and MCT2 mRNA level in the hippocampus were noted. Interestingly, strong MCT1 and MCT2 protein expression was found in peri-lesional macrophages/microglia and in an isolectin B4+/S100β+ cell population in the corpus callosum. In vitro, MCT1 and MCT2 protein expression was observed in the N11 microglial cell line, whereas an enhancement of MCT1 expression by tumor necrosis factor-α (TNF-α) was shown in these cells. Modulation of MCT expression in microglia suggests that these transporters may help sustain microglial functions during recovery from focal brain ischemia. Overall, our study indicates that changes in MCT expression around and also away from the ischemic area, both at the mRNA and protein levels, are a part of the metabolic adaptations taking place in the brain after ischemia.
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Defries, Danielle, and Michelle Beltran. "Short Chain Fatty Acid Transporter/Receptor Expression and Signaling in Enteric Glial Cells." Current Developments in Nutrition 4, Supplement_2 (May 29, 2020): 1201. http://dx.doi.org/10.1093/cdn/nzaa057_017.
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Abstract Objectives The enteric nervous system (ENS) independently coordinates gastrointestinal functions such as motility, secretion, and absorption. Enteric glial cells (EGCs), the largest group of cells within the ENS, secrete neurotrophic factors that support enteric neurons and epithelial growth factors that promote integrity of the intestinal epithelial barrier. Although numerous studies have examined the effect of short chain fatty acids (SCFAs) on functional properties of several intestinal cell types, including enterocytes, enteroendocrine cells, and gut immune cells, no studies to date have examined if and how SCFA influence EGCs. We sought to determine: (1) if EGCs have the capacity to respond to SCFAs; (2) signaling pathways downstream of SCFA transporters/receptors are active in EGCs. Methods Experiments were performed in a stably transformed enteroglial cell line (Ruhl et al., 1998). Cells were treated with propionate (0–10 mM), butyrate (0–5 mM), AR420626 (an FFAR3 agonist), or an FFAR2 agonist. Activation of transporters and receptors was assessed using Western blotting for acetylation and phosphorylation state of proteins downstream of the receptors. Expression of SCFA transporters and receptors was assessed using quantitative PCR. Results Basal expression of monocarboxylate transporter (MCT)-1 and MCT-4, as well as the G-protein coupled receptors FFAR2 and FFAR3 was detected, with expression levels of MCT-1 the highest. GPR109a and Olfr920 were not present in these cells. Butyrate treatment for 2 hours significantly elevated levels of acetylated histone H2B and H3 (P < 0.05), but not histone H2A, suggesting that this SCFA is transported across the plasma membrane to exert intracellular effects. Neither SCFAs nor AR420626 blocked forskolin-induced phosphorylation of protein kinase A (PKA), suggesting that FFAR3 signaling is not active in EGCs. Butyrate, but not the FFAR2 agonist, significantly increased phosphorylation of protein kinase C (PKC) (P < 0.05), suggesting that signaling pathways independent of FFAR2 are triggered by SCFA in EGCs. Conclusions Our preliminary evidence suggests that SCFAs are internalized by EGCs and affect intracellular signaling events. Future studies will determine the implications of histone deacetylation and PKC activation by SCFA on EGC function. Funding Sources University of Winnipeg Major Research Grant.
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Hatta, Hideo, Mio Tonouchi, Dragana Miskovic, Yuxiang Wang, John J. Heikkila, and Arend Bonen. "Tissue-specific and isoform-specific changes in MCT1 and MCT4 in heart and soleus muscle during a 1-yr period." American Journal of Physiology-Endocrinology and Metabolism 281, no. 4 (October 1, 2001): E749—E756. http://dx.doi.org/10.1152/ajpendo.2001.281.4.e749.
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We examined the postnatal changes ( days 10, 36, 84, 160, 365) of monocarboxylate transporters (MCT)1 and MCT4 in rat heart and soleus muscle. In the heart, MCT1 protein and mRNA remained unaltered from day 10 until 1 yr of age. Both MCT4 protein and mRNA in the heart were detected at 10 days of age, but the MCT4 protein and transcript were not detected thereafter. In the soleus muscle, MCT1 protein (+38%) and mRNA (+136%) increased during the first 84 days and remained stable until 1 yr of age. In contrast, soleus MCT4 protein decreased by 90% over the course of 1 yr, with the most rapid decrease (−60%) occurring by day 84 ( P < 0.05). At the same time, MCT4 mRNA was increased by 74% from days 10to 84 ( P < 0.05), remaining stable thereafter. In conclusion, developmental changes in MCT transport proteins are tissue specific and isoform specific. Furthermore, it appears that MCT1 expression in the heart and MCT1 and MCT4 expression in the soleus are regulated by pretranslational processes, whereas posttranscriptional processes regulate MCT4 expression in the soleus muscle.
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Azevedo-Silva, João, Odília Queirós, Ana Ribeiro, Fátima Baltazar, Ko H. Young, Peter L. Pedersen, Ana Preto, and Margarida Casal. "The cytotoxicity of 3-bromopyruvate in breast cancer cells depends on extracellular pH." Biochemical Journal 467, no. 2 (April 2, 2015): 247–58. http://dx.doi.org/10.1042/bj20140921.
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Although the anti-cancer properties of 3BP (3-bromopyruvate) have been described previously, its selectivity for cancer cells still needs to be explained [Ko et al. (2001) Cancer Lett. 173, 83–91]. In the present study, we characterized the kinetic parameters of radiolabelled [14C] 3BP uptake in three breast cancer cell lines that display different levels of resistance to 3BP: ZR-75-1 < MCF-7 < SK-BR-3. At pH 6.0, the affinity of cancer cells for 3BP transport correlates with their sensitivity, a pattern that does not occur at pH 7.4. In the three cell lines, the uptake of 3BP is dependent on the protonmotive force and is decreased by MCTs (monocarboxylate transporters) inhibitors. In the SK-BR-3 cell line, a sodium-dependent transport also occurs. Butyrate promotes the localization of MCT-1 at the plasma membrane and increases the level of MCT-4 expression, leading to a higher sensitivity for 3BP. In the present study, we demonstrate that this phenotype is accompanied by an increase in affinity for 3BP uptake. Our results confirm the role of MCTs, especially MCT-1, in 3BP uptake and the importance of cluster of differentiation (CD) 147 glycosylation in this process. We find that the affinity for 3BP transport is higher when the extracellular milieu is acidic. This is a typical phenotype of tumour microenvironment and explains the lack of secondary effects of 3BP already described in in vivo studies [Ko et al. (2004) Biochem. Biophys. Res. Commun. 324, 269–275].
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Moore, Nigel P., Catherine A. Picut, and Jeffrey H. Charlap. "Localisation of Lactate Transporters in Rat and Rabbit Placentae." International Journal of Cell Biology 2016 (2016): 1–6. http://dx.doi.org/10.1155/2016/2084252.
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The distribution of monocarboxylate transporter (MCT) isoforms 1 and 4, which mediate the plasmalemmal transport of l-lactic and pyruvic acids, has been identified in the placentae of rats and rabbits at different ages of gestation. Groups of three pregnant Sprague-Dawley rats and New Zealand White rabbits were sacrificed on gestation days (GD) 11, 14, 18, or 20 and on GD 13, 18, or 28, respectively. Placentae were removed and processed for immunohistochemical detection of MCT1 and MCT4. In the rat, staining for MCT1 was associated with lakes and blood vessels containing enucleated red blood cells (maternal vessels) while staining for MCT4 was associated with vessels containing nucleated red blood cells (embryofoetal vessels). In the rabbit, staining for MCT1 was associated with blood vessels containing nucleated red blood cells while staining for MCT4 was associated with vessels containing enucleated red blood cells. Strength of staining for MCT1 decreased during gestation in both species, but that for MCT4 was stronger than that for MCT1 and was consistent between gestation days. The results imply an opposite polarity of MCT1 and MCT4 across the trophoblast between rat and rabbit.
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Thomas, C., S. Perrey, K. Lambert, G. Hugon, D. Mornet, and J. Mercier. "Monocarboxylate transporters, blood lactate removal after supramaximal exercise, and fatigue indexes in humans." Journal of Applied Physiology 98, no. 3 (March 2005): 804–9. http://dx.doi.org/10.1152/japplphysiol.01057.2004.
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The present study investigated whether muscular monocarboxylate transporter (MCT) 1 and 4 contents are related to the blood lactate removal after supramaximal exercise, fatigue indexes measured during different supramaximal exercises, and muscle oxidative parameters in 15 humans with different training status. Lactate recovery curves were obtained after a 1-min all-out exercise. A biexponential time function was then used to determine the velocity constant of the slow phase (γ2), which denoted the blood lactate removal ability. Fatigue indexes were calculated during 1-min all-out (FIAO) and repeated 10-s (FISprint) cycling sprints. Biopsies were taken from the vastus lateralis muscle. MCT1 and MCT4 contents were quantified by Western blots, and maximal muscle oxidative capacity ( Vmax) was evaluated with pyruvate + malate and glutamate + malate as substrates. The results showed that the blood lactate removal ability (i.e., γ2) after a 1-min all-out test was significantly related to MCT1 content ( r = 0.70, P < 0.01) but not to MCT4 ( r = 0.50, P > 0.05). However, greater MCT1 and MCT4 contents were negatively related with a reduction of blood lactate concentration at the end of 1-min all-out exercise ( r = −0.56, and r = −0.61, P < 0.05, respectively). Among skeletal muscle oxidative indexes, we only found a relationship between MCT1 and glutamate + malate Vmax ( r = 0.63, P < 0.05). Furthermore, MCT1 content, but not MCT4, was inversely related to FIAO ( r = −0.54, P < 0.05) and FISprint ( r = −0.58, P < 0.05). We concluded that skeletal muscle MCT1 expression was associated with the velocity constant of net blood lactate removal after a 1-min all-out test and with the fatigue indexes. It is proposed that MCT1 expression may be important for blood lactate removal after supramaximal exercise based on the existence of lactate shuttles and, in turn, in favor of a better tolerance to muscle fatigue.
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Green, Howard J., Eric Bombardier, Todd A. Duhamel, Riley D. Stewart, A. Ross Tupling, and Jing Ouyang. "Metabolic, enzymatic, and transporter responses in human muscle during three consecutive days of exercise and recovery." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 295, no. 4 (October 2008): R1238—R1250. http://dx.doi.org/10.1152/ajpregu.00171.2008.
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This study investigated the responses in substrate- and energy-based properties to repetitive days of prolonged submaximal exercise and recovery. Twelve untrained volunteers (V̇o2peak = 44.8 ± 2.0 ml·kg−1·min−1, mean ± SE) cycled (∼60 V̇o2peak) on three consecutive days followed by 3 days of recovery. Tissue samples were extracted from the vastus lateralis both pre- and postexercise on day 1 (E1), day 3 (E3), and during recovery (R1, R2, R3) and were analyzed for changes in metabolism, substrate, and enzymatic and transporter responses. For the metabolic properties (mmol/kg−1 dry wt), exercise on E1 resulted in reductions ( P < 0.05) in phosphocreatine (PCr; 80 ± 1.9 vs. 41.2 ± 3.0) and increases ( P < 0.05) in inosine monophosphate (IMP; 0.13 ± 0.01 vs. 0.61 ± 0.2) and lactate (3.1 ± 0.4 vs. 19.2 ± 4.3). At E3, both IMP and lactate were lower ( P < 0.05) during exercise. For the transporters, the experimental protocol resulted in a decrease ( P < 0.05) in glucose transporter-1 (GLUT1; 29% by R1), an increase in GLUT4 (29% by E3), and increases ( P < 0.05) for both monocarboxylate transporters (MCT) (for MCT1, 23% by R2 and for MCT4, 18% by R1). Of the mitochondrial and cytosolic enzyme activities examined, cytochrome c oxidase (COX), and hexokinase were both reduced ( P < 0.05) by exercise at E1 and in the case of hexokinase and phosphorylase by exercise on E3. With the exception at COX, which was lower ( P < 0.05) at R1, no differences in enzyme activities existed at rest between E, E3, and recovery days. Results suggest that the glucose and lactate transporters are among the earliest adaptive responses of substrate and metabolic properties studied to the sudden onset of regular low-intensity exercise.
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Elizondo-Vega, Roberto, Karina Oyarce, Magdiel Salgado, María José Barahona, Antonia Recabal, Patricio Ordenes, Sergio López, Roxana Pincheira, Patricia Luz-Crawford, and María Angeles García-Robles. "Inhibition of Hypothalamic MCT4 and MCT1–MCT4 Expressions Affects Food Intake and Alters Orexigenic and Anorexigenic Neuropeptide Expressions." Molecular Neurobiology 57, no. 2 (October 2, 2019): 896–909. http://dx.doi.org/10.1007/s12035-019-01776-6.
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Abstract Feeding behavior regulation is a complex process, which depends on the central integration of different signals, such as glucose, leptin, and ghrelin. Recent studies have shown that glial cells known as tanycytes that border the basal third ventricle (3V) detect glucose and then use glucose-derived signaling to inform energy status to arcuate nucleus (ARC) neurons to regulate feeding behavior. Monocarboxylate transporters (MCT) 1 and MCT4 are localized in the cellular processes of tanycytes, which could facilitate monocarboxylate release to orexigenic and anorexigenic neurons. We hypothesize that MCT1 and MCT4 inhibitions could alter the metabolic communication between tanycytes and ARC neurons, affecting feeding behavior. We have previously shown that MCT1 knockdown rats eat more and exhibit altered satiety parameters. Here, we generate MCT4 knockdown rats and MCT1–MCT4 double knockdown rats using adenovirus-mediated transduction of a shRNA into the 3V. Feeding behavior was evaluated in MCT4 and double knockdown animals, and neuropeptide expression in response to intracerebroventricular glucose administration was measured. MCT4 inhibition produced a decrease in food intake, contrary to double knockdown. MCT4 inhibition was accompanied by a decrease in eating rate and mean meal size and an increase in mean meal duration, parameters that are not changed in the double knockdown animals with exception of eating rate. Finally, we observed a loss in glucose regulation of orexigenic neuropeptides and abnormal expression of anorexigenic neuropeptides in response to fasting when these transporters are inhibited. Taken together, these results indicate that MCT1 and MCT4 expressions in tanycytes play a role in feeding behavior regulation.
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Bonen, Arend, Mio Tonouchi, Dragana Miskovic, Catherine Heddle, John J. Heikkila, and Andrew P. Halestrap. "Isoform-specific regulation of the lactate transporters MCT1 and MCT4 by contractile activity." American Journal of Physiology-Endocrinology and Metabolism 279, no. 5 (November 1, 2000): E1131—E1138. http://dx.doi.org/10.1152/ajpendo.2000.279.5.e1131.
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We examined the isoform-specific regulation of monocarboxylate transporter (MCT)1 and MCT4 expression by contractile activity in red and white tibialis anterior muscles. After 1 and 3 wk of chronic muscle stimulation (24 h/day), MCT1 protein expression was increased in the red muscles (+78%, P< 0.05). In the white muscles, MCT1 was increased after 1 wk (+191%) and then was decreased after 3 wk. In the red muscle, MCT1 mRNA accumulation was increased only after 3 wk (+21%; P < 0.05). In the white muscle, MCT1 mRNA was increased after 1 wk (+30%; P < 0.05) and 3 wk (+15%; P < 0.05). MCT4 protein was not altered in either the red or white muscles after 1 or 3 wk. MCT4 mRNA was transiently lowered (∼15%) in both muscles in the 1st wk, but MCT4 mRNA levels were back to control levels after 3 wk. In conclusion, chronic contractile activity induces the expression of MCT1 but not MCT4. This increase in MCT1 alone was sufficient to increase lactate uptake from the circulation.
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Trajkovic-Arsic, Marija, Theo J. Visser, Veerle M. Darras, Edith C. H. Friesema, Bernhard Schlott, Jens Mittag, Karl Bauer, and Heike Heuer. "Consequences of Monocarboxylate Transporter 8 Deficiency for Renal Transport and Metabolism of Thyroid Hormones in Mice." Endocrinology 151, no. 2 (February 1, 2010): 802–9. http://dx.doi.org/10.1210/en.2009-1053.
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Patients carrying inactivating mutations in the gene encoding the thyroid hormone transporting monocarboxylate transporter (MCT)-8 suffer from a severe form of psychomotor retardation and exhibit abnormal serum thyroid hormone levels. The thyroidal phenotype characterized by high-serum T3 and low-serum T4 levels is also found in mice mutants deficient in MCT8 although the cause of these abnormalities is still unknown. Here we describe the consequences of MCT8 deficiency for renal thyroid hormone transport, metabolism, and function by studying MCT8 null mice and wild-type littermates. Whereas serum and urinary parameters do not indicate a strongly altered renal function, a pronounced induction of iodothyronine deiodinase type 1 expression together with increased renal T3 and T4 content point to a general hyperthyroid state of the kidneys in the absence of MCT8. Surprisingly, accumulation of peripherally injected T4 and T3 into the kidneys was found to be enhanced in the absence of MCT8, indicating that MCT8 deficiency either directly interferes with the renal efflux of thyroid hormones or activates indirectly other renal thyroid hormone transporters that preferentially mediate the renal uptake of thyroid hormones. Our findings indicate that the enhanced uptake and accumulation of T4 in the kidneys of MCT8 null mice together with the increased renal conversion of T4 into T3 by increased renal deiodinase type 1 activities contributes to the generation of the low-serum T4 and the increase in circulating T3 levels, a hallmark of MCT8 deficiency.
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Bishop, David, Johann Edge, Claire Thomas, and Jacques Mercier. "High-intensity exercise acutely decreases the membrane content of MCT1 and MCT4 and buffer capacity in human skeletal muscle." Journal of Applied Physiology 102, no. 2 (February 2007): 616–21. http://dx.doi.org/10.1152/japplphysiol.00590.2006.
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The regulation of intracellular pH during intense muscle contractions occurs via a number of different transport systems [e.g., monocarboxylate transporters (MCTs)] and via intracellular buffering (βmin vitro). The aim of this study was to investigate the effects of an acute bout of high-intensity exercise on both MCT relative abundance and βmin vitro in humans. Six active women volunteered for this study. Biopsies of the vastus lateralis were obtained at rest and immediately after 45 s of exercise at 200% of maximum O2 uptake. βmin vitro was determined by titration, and MCT relative abundance was determined in membrane preparations by Western blots. High-intensity exercise was associated with a significant decrease in both MCT1 (−24%) and MCT4 (−26%) and a decrease in βmin vitro (−11%; 135 ± 3 to 120 ± 2 μmol H+·g dry muscle−1·pH−1; P < 0.05). These changes were consistently observed in all subjects, and there was a significant correlation between changes in MCT1 and MCT4 relative abundance ( R2 = 0.92; P < 0.05). In conclusion, a single bout of high-intensity exercise decreased both MCT relative abundance in membrane preparations and βmin vitro. Until the time course of these changes has been established, researchers should consider the possibility that observed training-induced changes in MCT and βmin vitro may be influenced by the acute effects of the last exercise bout, if the biopsy is taken soon after the completion of the training program. The implications that these findings have for lactate (and H+) transport following acute, exhaustive exercise warrant further investigation.
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Ovens, Matthew J., Christine Manoharan, Marieangela C. Wilson, Clarey M. Murray, and Andrew P. Halestrap. "The inhibition of monocarboxylate transporter 2 (MCT2) by AR-C155858 is modulated by the associated ancillary protein." Biochemical Journal 431, no. 2 (September 28, 2010): 217–25. http://dx.doi.org/10.1042/bj20100890.
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In mammalian cells, MCTs (monocarboxylate transporters) require association with an ancillary protein to enable plasma membrane expression of the active transporter. Basigin is the preferred binding partner for MCT1, MCT3 and MCT4, and embigin for MCT2. In rat and rabbit erythrocytes, MCT1 is associated with embigin and basigin respectively, but its sensitivity to inhibition by AR-C155858 was found to be identical. Using RT (reverse transcription)–PCR, we have shown that Xenopus laevis oocytes contain endogenous basigin, but not embigin. Co-expression of exogenous embigin was without effect on either the expression of MCT1 or its inhibition by AR-C155858. In contrast, expression of active MCT2 at the plasma membrane of oocytes was significantly enhanced by co-expression of exogenous embigin. This additional transport activity was insensitive to inhibition by AR-C155858 unlike that by MCT2 expressed with endogenous basigin that was potently inhibited by AR-C155858. Chimaeras and C-terminal truncations of MCT1 and MCT2 were also expressed in oocytes in the presence and absence of exogenous embigin. L-Lactate Km values for these constructs were determined and revealed that the TM (transmembrane) domains of an MCT, most probably TM7–TM12, but not the C-terminus, are the major determinants of L-lactate affinity, whereas the associated ancillary protein has little or no effect. Inhibitor titrations of lactate transport by these constructs indicated that embigin modulates MCT2 sensitivity to AR-C155858 through interactions with both the intracellular C-terminus and TMs 3 and 6 of MCT2. The C-terminus of MCT2 was found to be essential for its expression with endogenous basigin.
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Gündel, Daniel, Masoud Sadeghzadeh, Winnie Deuther-Conrad, Barbara Wenzel, Paul Cumming, Magali Toussaint, Friedrich-Alexander Ludwig, et al. "Preclinical Evaluation of [18F]FACH in Healthy Mice and Piglets: An 18F-Labeled Ligand for Imaging of Monocarboxylate Transporters with PET." International Journal of Molecular Sciences 22, no. 4 (February 6, 2021): 1645. http://dx.doi.org/10.3390/ijms22041645.
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The expression of monocarboxylate transporters (MCTs) is linked to pathophysiological changes in diseases, including cancer, such that MCTs could potentially serve as diagnostic markers or therapeutic targets. We recently developed [18F]FACH as a radiotracer for non-invasive molecular imaging of MCTs by positron emission tomography (PET). The aim of this study was to evaluate further the specificity, metabolic stability, and pharmacokinetics of [18F]FACH in healthy mice and piglets. We measured the [18F]FACH plasma protein binding fractions in mice and piglets and the specific binding in cryosections of murine kidney and lung. The biodistribution of [18F]FACH was evaluated by tissue sampling ex vivo and by dynamic PET/MRI in vivo, with and without pre-treatment by the MCT inhibitor α-CCA-Na or the reference compound, FACH-Na. Additionally, we performed compartmental modelling of the PET signal in kidney cortex and liver. Saturation binding studies in kidney cortex cryosections indicated a KD of 118 ± 12 nM and Bmax of 6.0 pmol/mg wet weight. The specificity of [18F]FACH uptake in the kidney cortex was confirmed in vivo by reductions in AUC0–60min after pre-treatment with α-CCA-Na in mice (−47%) and in piglets (−66%). [18F]FACH was metabolically stable in mouse, but polar radio-metabolites were present in plasma and tissues of piglets. The [18F]FACH binding potential (BPND) in the kidney cortex was approximately 1.3 in mice. The MCT1 specificity of [18F]FACH uptake was confirmed by displacement studies in 4T1 cells. [18F]FACH has suitable properties for the detection of the MCTs in kidney, and thus has potential as a molecular imaging tool for MCT-related pathologies, which should next be assessed in relevant disease models.
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Kubelt, Carolin, Sönke Peters, Hajrullah Ahmeti, Monika Huhndorf, Lukas Huber, Gesa Cohrs, Jan-Bernd Hövener, Olav Jansen, Michael Synowitz, and Janka Held-Feindt. "Intratumoral Distribution of Lactate and the Monocarboxylate Transporters 1 and 4 in Human Glioblastoma Multiforme and Their Relationships to Tumor Progression-Associated Markers." International Journal of Molecular Sciences 21, no. 17 (August 29, 2020): 6254. http://dx.doi.org/10.3390/ijms21176254.
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(1) Background: Metabolic reprogramming has been postulated to be one of the hallmarks of cancer, thus representing a promising therapeutic target also in glioblastoma multiforme (GBM). Hypoxic tumor cells produce lactate, and monocarboxylate transporters (MCTs) play an important role in its distribution; (2) Methods: We examined the distribution of lactate by multi voxel magnetic resonance spectroscopic imaging and ELISA in glioblastoma multiforme (GBM) patients. In addition, we investigated the expression and cellular localization of MCT1, MCT4, and of several markers connected to tumor progression by quantitative PCR and immunofluorescence double-staining in human GBM ex vivo tissues; (3) Results: The highest lactate concentration was found at the center of the vital parts of the tumor. Three main GBM groups could be distinguished according to their regional gene expression differences of the investigated genes. MCT1 and MCT4 were found on cells undergoing epithelial to mesenchymal transition and on tumor stem-like cells. GBM cells revealing an expression of cellular dormancy markers, showed positive staining for MCT4; (4) Conclusion: Our findings indicate the existence of individual differences in the regional distribution of MCT1 and MCT4 and suggest that both transporters have distinct connections to GBM progression processes, which could contribute to the drug resistance of MCT-inhibitors.
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Fernández, Mercedes, Micaela Pannella, Vito Antonio Baldassarro, Alessandra Flagelli, Giuseppe Alastra, Luciana Giardino, and Laura Calzà. "Thyroid Hormone Signaling in Embryonic Stem Cells: Crosstalk with the Retinoic Acid Pathway." International Journal of Molecular Sciences 21, no. 23 (November 25, 2020): 8945. http://dx.doi.org/10.3390/ijms21238945.
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While the role of thyroid hormones (THs) during fetal and postnatal life is well-established, their role at preimplantation and during blastocyst development remains unclear. In this study, we used an embryonic stem cell line isolated from rat (RESC) to study the effects of THs and retinoic acid (RA) on early embryonic development during the pre-implantation stage. The results showed that THs play an important role in the differentiation/maturation processes of cells obtained from embryoid bodies (EB), with thyroid hormone nuclear receptors (TR) (TRα and TRβ), metabolic enzymes (deiodinases 1, 2, 3) and membrane transporters (Monocarboxylate transporters -MCT- 8 and 10) being expressed throughout in vitro differentiation until the Embryoid body (EB) stage. Moreover, thyroid hormone receptor antagonist TR (1-850) impaired RA-induced neuroectodermal lineage specification. This effect was significantly higher when cells were treated with retinoic acid (RA) to induce neuroectodermal lineage, studied through the gene and protein expression of nestin, an undifferentiated progenitor marker from the neuroectoderm lineage, as established by nestin mRNA and protein regulation. These results demonstrate the contribution of the two nuclear receptors, TR and RA, to the process of neuroectoderm maturation of the in vitro model embryonic stem cells obtained from rat.