Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Short‐Chain Fatty Acid Transporters: Role in Colonic Homeostasis

Sathish Sivaprakasam, Yangzom D. Bhutia, Shengping Yang, Vadivel Ganapathy

10.1002/cphy.c170014

Source: Volume 8, Issue 1, January 2018

Published online: December 2017

Full Article on Wiley Online Library



ABSTRACT

Short‐chain fatty acids (SCFA; acetate, propionate, and butyrate) are generated in colon by bacterial fermentation of dietary fiber. Though diffusion in protonated form is a significant route, carrier‐mediated mechanisms constitute the major route for the entry of SCFA in their anionic form into colonic epithelium. Several transport systems operate in cellular uptake of SCFA. MCT1 (SLC16A1) and MCT4 (SLC16A3) are H+‐coupled and mediate electroneutral transport of SCFA (H+: SCFA stoichiometry; 1:1). MCT1 is expressed both in the apical membrane and basolateral membrane of colonic epithelium whereas MCT4 specifically in the basolateral membrane. SMCT1 (SLC5A8) and SMCT2 (SLC5A12) are Na+‐coupled; SMCT1‐mediated transport is electrogenic (Na+: SCFA stoichiometry; 2:1) whereas SMCT2‐mediated transport is electroneutral (Na+: SCFA stoichiometry; 1:1). SMCT1 and SMCT2 are expressed exclusively in the apical membrane. An anion‐exchange mechanism also operates in the apical membrane in which SCFA entry in anionic form is coupled to bicarbonate efflux; the molecular identity of this exchanger however remains unknown. All these transporters are subject to regulation, notably by their substrates themselves; this process involves cell‐surface receptors with SCFA as signaling molecules. There are significant alterations in the expression of these transporters in ulcerative colitis and colon cancer. The tumor‐associated changes occur via transcriptional regulation by p53 and HIF1α and by promoter methylation. As SCFA are obligatory for optimal colonic health, the transporters responsible for the entry and transcellular transfer of these bacterial products in colonic epithelium are critical determinants of colonic function under physiological conditions and in disease states. © 2018 American Physiological Society. Compr Physiol 8:299‐314, 2018.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Relationship between MCT1 (SLC16A1) mRNA expression levels in tumor tissues and overall survival of patients with cancer of colon and rectum. (A) Cancers of colon and rectum combined; (B) cancer of colon; and (C) cancer of rectum. OS, overall survival. In patients with rectal cancer, higher expression of SLC16A1 correlates significantly with improved overall survival. The trend, but not statistically significant, of positive correlation between SLC16A1 expression levels and overall survival is observed when data for patients with colon cancer and rectal cancer are combined. When data for patients with colon cancer are analyzed separately, there is no significant correlation between SLC16A1 expression levels and overall survival.
Figure 2. Figure 2. Relationship between SMCT1 (SLC5A8) mRNA expression levels in tumor tissues and overall survival of patients with cancer of colon and rectum. (A) Cancers of colon and rectum combined; (B) cancer of colon; and (C) cancer of rectum. OS, overall survival. There is no statistically significant correlation between SLC5A8 mRNA levels in tumor tissues and overall survival of the patients. There is a weak correlation between the two parameters when data for colon cancer alone are analyzed, but this correlation seems to indicate that higher expression of SLC5A8 is associated with lower overall survival, a trend that goes against the tumor‐suppressive function of SLC5A8.
Figure 3. Figure 3. Polarized expression of short‐chain fatty acid transporters in colonic epithelium. SCFA, short‐chain fatty acids; MCT1, monocarboxylate transporter 1 (SLC16A1); MCT4, monocarboxylate transporter 4 (SLC16A3); SMCT1, sodium‐coupled monocarboxylate transporter 1 (SLC5A8); ABCG2, ATP binding cassette transporter, gene family G, member 2. CD147 is the chaperone (ancillary protein) for MCT1 and MCT4.


Figure 1. Relationship between MCT1 (SLC16A1) mRNA expression levels in tumor tissues and overall survival of patients with cancer of colon and rectum. (A) Cancers of colon and rectum combined; (B) cancer of colon; and (C) cancer of rectum. OS, overall survival. In patients with rectal cancer, higher expression of SLC16A1 correlates significantly with improved overall survival. The trend, but not statistically significant, of positive correlation between SLC16A1 expression levels and overall survival is observed when data for patients with colon cancer and rectal cancer are combined. When data for patients with colon cancer are analyzed separately, there is no significant correlation between SLC16A1 expression levels and overall survival.


Figure 2. Relationship between SMCT1 (SLC5A8) mRNA expression levels in tumor tissues and overall survival of patients with cancer of colon and rectum. (A) Cancers of colon and rectum combined; (B) cancer of colon; and (C) cancer of rectum. OS, overall survival. There is no statistically significant correlation between SLC5A8 mRNA levels in tumor tissues and overall survival of the patients. There is a weak correlation between the two parameters when data for colon cancer alone are analyzed, but this correlation seems to indicate that higher expression of SLC5A8 is associated with lower overall survival, a trend that goes against the tumor‐suppressive function of SLC5A8.


Figure 3. Polarized expression of short‐chain fatty acid transporters in colonic epithelium. SCFA, short‐chain fatty acids; MCT1, monocarboxylate transporter 1 (SLC16A1); MCT4, monocarboxylate transporter 4 (SLC16A3); SMCT1, sodium‐coupled monocarboxylate transporter 1 (SLC5A8); ABCG2, ATP binding cassette transporter, gene family G, member 2. CD147 is the chaperone (ancillary protein) for MCT1 and MCT4.
References
 1.Abbott BL. ABCG2 (BCRP): A cytoprotectant in normal and malignant stem cells. Clin Adv Hematol Oncol 4: 63‐72, 2006.
 2.Al‐Mosauwi H, Ryan E, McGrane A, Riveros‐Beltran S, Walpole C, Dempsey E, Courtney D, Fearon N, Winter D, Baird A, Stewart G. Differential protein abundance of a basolateral MCT1 transporter in the human gastrointestinal tract. Cell Biol Int 40: 1303‐1312, 2016.
 3.Aschenbach JR, Penner GB, Stumpff F, Gabel G. Ruminant Nutrition Symposium: Role of fermentation acid absorption in the regulation of ruminal pH. J Anim Sci 89: 1092‐1107, 2011.
 4.Babu E, Ananth S, Veeranan‐Karmegam R, Coothankandaswamy V, Smith SB, Boettger T, Ganapathy V, Martin PM. Transport via SLC5A8 (SMCT1) is obligatory for 2‐oxothiazolidine‐4‐carboxylate to enhance glutathione production in retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 52: 5749‐5757, 2011.
 5.Babu E, Ramachandran S, Coothankandaswamy V, Elangovan S, Prasad PD, Ganapathy V, Thangaraju M. Role of SLC5A8, a plasma membrane transporter and a tumor suppressor, in the antitumor activity of dichloroacetate. Oncogene 30: 4026‐4037, 2011.
 6.Bhutia YD, Babu E, Ramachandran S, Yang S, Thangaraju M, Ganapathy V. SLC transporters as a novel class of tumour suppressors: Identity, function and molecular mechanisms. Biochem J 473: 1113‐1124, 2016.
 7.Bhutia YD, Ogura J, Sivaprakasam S, Ganapathy V. Gut microbiome and colon cancer: Role of bacterial metabolites and their molecular targets in the host. Curr Colorectal Cancer Rep. 13: 111‐118, 2017.
 8.Binder HJ. Role of colonic short‐chain fatty acid transport in diarrhea. Annu Rev Physiol 72: 297‐313, 2010.
 9.Binder HJ, Rajendran V, Sadasivan V, Geibel JP. Bicarbonate secretion: A neglected aspect of colonic ion transport. J Clin Gastroenterol 39(Suppl. 2): S53‐S58, 2005.
 10.Borthakur A, Anbazhagan AN, Kumar A, Raheja G, Singh V, Ramaswamy K, Dudeja PK. The probiotic Lactobacillus plantarum counteracts TNF‐α‐induced downregulation of SMCT1 expression and function. Am J Physiol Gastrointest Liver Physiol 299: G928‐G934, 2010.
 11.Borthakur A, Gill RK, Hodges K, Ramaswamy K, Hecht G, Dudeja PK. Enteropathogenic Escherichia coli inhibits butyrate uptake in Caco‐2 cells by altering the apical membrane MCT1 level. Am J Physiol Gastrointest Liver Physiol 290: G30‐G35, 2006.
 12.Borthakur A, Priyamvada S, Kumar A, Natarajan AA, Gill RK, Alrefai WA, Dudeja PK. A novel nutrient sensing mechanism underlies substrate‐induced regulation of monocarboxylate transporter 1. Am J Physiol Gastrointest Liver Physiol 303: G1126‐G1133, 2012.
 13.Borthakur A, Saksena S, Gill RK, Alrefai WA, Ramaswamy K, Dudeja PK. Regulation of monocarboxylate transporter 1 (MCT1) promoter by butyrate in human intestinal epithelial cells: Involvement of NF‐κB pathway. J Cell Biochem 103: 1452‐1463, 2008.
 14.Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, Muir AI, Wigglesworth MJ, Kinghorn I, Fraser NJ, Pike NB, Strum JC, Steplewski KM, Murdock PR, Holder JC, Marshall FH, Szekeres PG, Wilson S, Ignar DM, Foord SM, Wise A, Dowell SJ. The orphan G protein‐coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem 278: 11312‐11319, 2003.
 15.Bultman SJ. The microbiome and its potential as a cancer preventive intervention. Semin Oncol 43: 97‐106, 2016.
 16.Buyse M, Sitaraman SV, Liu X, Bado A, Merlin D. Luminal leptin enhances CD147/MCT1‐mediated uptake of butyrate in the human intestinal cell line Caco2‐BBE. J Biol Chem 277: 28182‐28190, 2002.
 17.Coady MJ, Chang MH, Charron FM, Plata C, Wallendorff B, Sah JF, Markowitz SD, Romero MF, Lapointe JY. The human tumour suppressor gene SLC5A8 expresses a Na+‐coupled monocarboxylate transporter. J Physiol 557: 719‐731, 2004.
 18.Coothankandaswamy V, Elangovan S, Singh N, Prasad PD, Thangaraju M, Ganapathy V. The plasma membrane transporter SLC5A8 suppresses tumour progression through depletion of survivin without involving its transport function. Biochem J 450: 169‐178, 2013.
 19.Cresci G, Nagy LE, Ganapathy V. Lactobacillus GG and tributyrin supplementation reduce antibiotic‐induced intestinal injury. JPEN J Parenter Enteral Nutr 37: 763‐774, 2013.
 20.Cresci GA, Thangaraju M, Mellinger JD, Liu K, Ganapathy V. Colonic gene expression in conventional and germ‐free mice with a focus on the butyrate receptor GPR109A and the butyrate transporter SLC5A8. J Gastrointest Surg 14: 449‐461, 2010.
 21.Cuff MA, Lambert DW, Shirazi‐Beechey SP. Substrate‐induced regulation of the human colonic monocarboxylate transporter, MCT1. J Physiol 539: 361‐371, 2002.
 22.Cuff MA, Shirazi‐Beechey SP. The human monocarboxylate transporter MCT1: Genomic organization and promoter analysis. Biochem Biophys Res Commun 292: 1048‐1056, 2002.
 23.Daly K, Sirazi‐Beechey SP. Microarray analysis of butyrate regulated genes in colonic epithelial cells. DNA Cell Biol 25: 49‐62, 2006.
 24.de Lau W, Barker N, Clevers H. WNT signaling in the normal intestine and colorectal cancer. Front Biosci 12: 471‐491, 2007.
 25.Ding XW, Wu JH, Jiang CP. ABCG2: A potential marker of stem cells and novel target in stem cell and cancer therapy. Life Sci 86: 631‐637, 2010.
 26.Doherty JR, Yang C, Scott KE, Cameron MD, Fallahi M, Li W, Hall MA, Amelio AL, Mishra JK, Li F, Tortosa M, Genau HM, Rounbehler RJ, Lu Y, Dang CV, Kumar KG, Butler AA, Bannister TD, Hooper AT, Unsal‐Kacmaz K, Roush WR, Cleveland JL. Blocking lactate export by inhibiting the Myc target MCT1 disables glycolysis and glutathione synthesis. Cancer Res 74: 908‐920, 2014.
 27.Doyle L, Ross DD. Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene 22: 7340‐7358, 2003.
 28.Drozdzik M, Groer C, Penski J, Lapczuk J, Ostrowski M, Lai Y, Prasad B, Unadkat JD, Siegmund W, Oswald S. Protein abundance of clinically relevant multidrug transporters along the entire length of the human intestine. Mol Pharm 11: 3547‐3555, 2014.
 29.Elangovan S, Pathania R, Ramachandran S, Ananth S, Padia RN, Srinivas SR, Babu E, Hawthorn L, Schoenlein PV, Boettger T, Smith SB, Prasad PD, Ganapathy V, Thangaraju M. Molecular mechanism of SLC5A8 inactivation in breast cancer. Mol Cell Biol 33: 3920‐3935, 2013.
 30.Englund G, Rorsman F, Ronnblom A, Karlbom U, Lazorova L, Grasjo J, Kindmark A, Artursson P. Regional levels of drug transporters along the human intestinal tract: Co‐expression of ABC and SLC transporters and comparison with Caco‐2 cells. Eur J Pharm Sci 29: 269‐277, 2006.
 31.Enokizono J, Kusuhara H, Sugiyama Y. Regional expression and activity of breast cancer resistance protein (Bcrp/Abcg2) in mouse intestine: Overlapping distribution with sulfotransferases. Drug Metab Dispos 35: 922‐928, 2007.
 32.Frank H, Groger N, Diener M, Becker C, Braun T, Boettger T. Lactaturia and loss of sodium‐dependent lactate uptake in the colon of SLC5A8‐deficient mice. J Biol Chem 283: 24729‐24737, 2008.
 33.Ganapathy V, Thangaraju M, Gopal E, Martin PM, Itagaki S, Miyauchi S, Prasad PD. Sodium‐coupled monocarboxylate transporters in normal tissues and in cancer. AAPS J 10: 193‐199, 2008.
 34.Ganapathy V, Thangaraju M, Prasad PD, Martin PM, Singh N. Transporters and receptors for short‐chain fatty acids as the molecular link between colonic bacteria and the host. Curr Opin Pharmacol 13: 869‐974, 2013.
 35.Ganapathy V, Thangaraju M, Prasad PD. Nutrient transporters in cancer: Relevance to Warburg hypothesis and beyond. Pharmacol Ther 121: 29‐40, 2009.
 36.Garcia CK, Goldstein JL, Pathak RK, Anderson RG, Brown MS. Molecular characterization of a membrane transporter for lactate, pyruvate, and other monocarboxylates: Implications for the Cori cycle. Cell 76: 865‐873, 1994.
 37.Garcia CK, Li X, Luna J, Francke U. cDNA cloning of the human monocarboxylate transporter 1 and chromosomal localization of the SLC16A1 locus to 1p13.2‐p12. Genomics 23: 500‐503, 1994.
 38.Gill RK, Saksena S, Alrefai WA, Sarwar Z, Goldstein JL, Carroll RE, Ramaswamy K, Dudeja PK. Expression and membrane localization of MCT isoforms along the length of the human intestine. Am J Physiol Cell Physiol 289: C846‐C852, 2005.
 39.Goncalves P, Araujo JR, Martel F. Characterization of butyrate uptake by nontransformed intestinal epithelial cell lines. J Membr Biol 240: 35‐46, 2011.
 40.Goncalves P, Gergorio I, Martel F. The short‐chain fatty acid butyrate is a substrate of breast cancer resistance protein. Am J Physiol Cell Physiol 301: C984‐C994, 2011.
 41.Goncalves P, Martel F. Butyrate and colorectal cancer: The role of butyrate transport. Curr Drug Metab 14: 994‐1008, 2013.
 42.Gopal E, Fei YJ, Miyauchi S, Zhuang L, Prasad PD, Ganapathy V. Sodium‐coupled and electrogenic transport of B‐complex vitamin nicotinic acid by Slc5a8, a member of the Na+/glucose co‐transporter gene family. Biochem J 388: 309‐316, 2005.
 43.Gopal E, Fei YJ, Sugawara M, Miyauchi S, Zhuang L, Martin PM, Smith SB, Prasad PD, Ganapathy V. Expression of Slc5a8 in kidney and its role in Na+‐coupled transport of lactate. J Biol Chem 279: 44522‐44532, 2004.
 44.Gopal E, Miyauchi S, Martin PM, Ananth S, Roon P, Smith SB, Ganapathy V. Transport of nicotinate and structurally related compounds by human SMCT1 (SLC5A8) and its relevance to drug transport in the mammalian intestinal tract. Pharm Res 24: 575‐584, 2007.
 45.Gopal E, Umapathy NS, Martin PM, Ananth S, Gnanaprakasam JP, Becker H, Wagner CA, Ganapathy V, Prasad PD. Cloning and functional characterization of human SMCT2 (SLC5A12) and expression pattern of the transporter in kidney. Biochim Biophys Acta 1768: 2690‐2697, 2007.
 46.Graham C, Gatherar I, Haslam I, Glanville M, Simmons NL. Expression and localization of monocarboxylate transporters and sodium/proton exchangers in bovine rumen epithelium. Am J Physiol Regul Integr Comp Physiol 292: R997‐F1007, 2007.
 47.Guile SD, Bantick JR, Cheshire DR, Cooper ME, Davis AM, Donald DK, Evans R, Eyssade C, Ferguson DD, Hill S, Hutchinson R, Ingall AH, Kingston LP, Martin I, Martin BP, Mohammed RT, Murray C, Perry MW, Reynolds RH, Thorne PV, Wilkinson DJ, Withnall J. Potent blockers of the monocarboxylate transporter MCT1: Novel immunomodulatory compounds. Bioorg Med Chem Lett 16: 2260‐2265, 2006.
 48.Gupta N, Martin PM, Miyauchi S, Ananth S, Herdman AV, Martindale RG, Podolsky R, Ganapathy V. Down‐regulation of BCRP/ABCG2 in colorectal and cervical cancer. Biochem Biophys Res Commun 343: 571‐577, 2006.
 49.Gupta N, Martin PM, Prasad PD, Ganapathy V. SLC5A8 (SMCT1)‐mediated transport of butyrate forms the basis for the tumor‐suppressive function of the transporter. Life Sci 78: 2419‐2425, 2006.
 50.Gurav A, Sivaprakasam S, Bhutia YD, Boettger T, Singh N, Ganapathy V. Slc5a8, a Na+‐coupled high‐affinity transporter for short‐chain fatty acids, is a conditional tumour suppressor in colon that protects against colitis and colon cancer under low‐fibre dietary conditions. Biochem J 469: 267‐278, 2015.
 51.Hadjiagapiou C, Borthakur A, Dahdal RY, Gill RK, Malakooti J, Ramaswamy K, Dedeja PK. Role of USF1 and USF2 as potential repressor proteins for human intestinal monocarboxylate transporter 1 promoter. Am J Physiol Gastrointest Liver Physiol 288: G1118‐G1126, 2005.
 52.Hadjiagapiou C, Schmidt L, Dudeja PK, Layden TJ, Ramaswamy K. Mechanisms of butyrate transport in Caco‐2 cells: Role of monocarboxylate transporter 1. Am J Physiol Gastrointest Liver Physiol 279: G775‐G780, 2000.
 53.Halestrap AP. The SLC16 gene family–‐Structure, role and regulation in health and disease. Mol Aspects Med 34: 337‐349, 2013.
 54.Hamer HM, Jonkers D, Venema K, Vanhoutvin S, Troost FJ, Brummer RJ. Review article: The role of butyrate on colonic function. Aliment Pharmacol Ther 27: 104‐119, 2008.
 55.Harig JM, Ng EK, Dudeja PK, Brasitus TA, Ramaswamy K. Transport of n‐butyrate into human colonic luminal membrane vesicles. Am J Physiol 271: G415‐G422, 1996.
 56.Havenaar R. Intestinal health functions of colonic microbial metabolites: A review. Benef Microbes 2: 103‐114, 2011.
 57.Huang Y, Lemieux MJ, Song J, Auer M, Wang DN. Structure and mechanism of the glycerol‐3‐phosphate transporter from Escherichia coli. Science 301: 616‐620, 2003.
 58.Itagaki S, Gopal E, Zhuang L, Fei YJ, Miyauchi S, Prasad PD, Ganapathy V. Interaction of ibuprofen and other structurally related NSAIDs with the sodium‐coupled monocarboxylate transporter SMCT1 (SLC5A8). Pharm Res 23: 1209‐1216, 2006.
 59.Iwanaga T, Takebe K, Kato I, Karaki S, Kuwahara A. Cellular expression of monocarboxylate transporters (MCT) in the digestive tract of the mouse, rat, and humans, with special reference to Slc5a8. Biomed Res 27: 243‐254, 2006.
 60.Jobin C. GPR109a: The missing link between microbiome and good health? Immunity 40: 8‐10, 2014.
 61.Kaji I, Iwanaga T, Watanabe M, Guth PH, Engel E, Kaunitz JD, Akiba Y. SCFA transport in rat duodenum. Am J Physiol Gastrointest Liver Physiol 308: G188‐G197, 2015.
 62.Kekuda R, Manoharan P, Baseler W, Sundaram U. Monocarboxylate transporter 4 mediated butyrate transport in a rat intestinal epithelial cell line. Dig Dis Sci 58: 660‐667, 2013.
 63.Kim CM, Goldstein JL, Brown MS. cDNA cloning of MEV, a mutant protein that facilitates cellular uptake of mevalonate, and identification of the point mutation responsible for its gain of function. J Biol Chem 267: 23113‐23121, 1992.
 64.Kirat D, Kondo K, Shimada R, Kato S. Dietary pectin up‐regulates monocarboxylate transporter 1 in the rat gastrointestinal tract. Exp Physiol 94: 422‐433, 2009.
 65.Kirat D, Masuoka J, Hayashi H, Iwano H, Yokota H, Taniyama H, Kato S. Monocarboxylate transporter 1 (MCT1) plays a direct role in short‐chain fatty acids absorption in caprine rumen. J Physiol 576: 635‐647, 2006.
 66.Kirk P, Wilson MC, Heddle C, Brown MH, Barclay AN, Halestrap AP. CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression. EMBO J 19: 3896‐3904, 2000.
 67.Kumar A, Alrefai WA, Borthakur A, Dudeja PK. Lactobacillus acidophilus counteracts enteropathogenic E. coli‐induced inhibition of butyrate uptake in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 309: G602‐G607, 2015.
 68.Lambert DW, Wood IS, Ellis A, Shirazi‐Beechey SP. Molecular changes in the expression of human colonic nutrient transporters during the transition from normalcy to malignancy. Br J Cancer 86: 1262‐1269, 2002.
 69.Le Poul E, Loison C, Struyf S, Springael JY, Lannoy V, Decobecq ME, Brezillon S, Dupriez V, Vassart G, Van Damme J, Parmentier M, Detheux M. Functional characterization of human receptors for short chain fatty acids and their rile in polymorphonuclear cell activation. J Biol Chem 278: 25481‐25489, 2003.
 70.Lean CB, Lee EJ. Genetic variations of the MCT4 (SLC16A3) gene in the Chinese and Indian populations of Singapore. Drug Metab Pharmacokinet 27: 456‐464, 2012.
 71.Lee T, Schwandner R, Swaminath G, Weiszmann J, Cardozo M, Greenberg J, Jaeckel P, Ge H, Wang Y, Jiao X, Liu J, Keyser F, Tian H, Li Y. Identification and functional characterization of allosteric agonists for the G protein‐coupled receptor FFA2. Mol Pharmacol 74: 1599‐1609, 2008.
 72.Lee Y, Morrison BM, Li Y, Lengacher S, Farah MH, Hoffman PN, Liu Y, Tsinglaia A, Jin L, Zhang PW, Pelerin L, Magistrett PJ, Rothstein JD. Oligodendroglia metabolically support axons and contribute to neurodegenaration. Nature 487: 443‐448, 2012.
 73.Lengacher S, Nehiri‐Sitayeb TN, Steiner N, Carneiro L, Favrod C, Preitner F, Thorens B, Stehle JC, Dix L, Pralong F, Magistretti PJ, Pellerin L. Resistance to diet‐induced obesity and associated metabolic perturbations in haploinsufficient monocarboxylate transporter 1 mice. PLoS One 8: e82505, 2013.
 74.Li H, Myeroff L, Smiraglia D, Romero MF, Pretlow TP, Kasturi L, Lutterbaugh J, Rerko RM, Casey G, Issa JP, Willis J, Wilson JK, Plass C, Markowitz SD. SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc Natl Acad Sci USA 100: 8412‐8417, 2003.
 75.Manoharan C, Wilson MC, Sessions RB, Halestrap AP. The role of charged residues in the transmembrane helices of monocarboxylate transporter 1 and its ancillary protein basigin in determining plasma membrane expression and catalytic activity. Mol Membr Biol 23: 486‐498, 2006.
 76.Marchiq I, Pouyssegur J. Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/H+ symporters. J Mol Med 94: 155‐171, 2016.
 77.Marquard J, Welters A, Buschmann T, Barthlen W, Vogelgesang S, Klee D, Krausch M, Raffel A, Otter S, Piemonti L, Mayatepek E, Otonkoski T, Lammert E, Meissner T. Association of exercise‐induced hyperinsulinaemic hypoglycemia with MCT1‐expressiong insulinoma. Diabetologia 56: 31‐35, 2013.
 78.Martin PM, Ananth S, Cresci G, Roon P, Smith SB, Ganapathy V. Expression and localization of GPR109A (PUMA‐G/HM74A) mRNA and protein in mammalian retinal pigment epithelium. Mol Vis 15: 362‐372, 2009.
 79.Martin PM, Gopal E, Ananth S, Zhuang L, Itagaki S, Prasad BM, Smith SB, Prasad PD, Ganapathy V. Identity of SMCT1 (SLC5A8) as a neuron‐specific Na+‐coupled transporter for active uptake of L‐lactate and ketone bodies in the brain. J Neurochem 98: 279‐288, 2006.
 80.Mascolo N, Rajendran VM, Binder HJ. Mechanism of short‐chain fatty acid uptake by apical membrane vesicles of rat distal colon. Gastroenterology 101: 331‐338, 1991.
 81.McFate T, Mohyeldin A, Lu H, Thakar J, Henriques J, Halim ND, Wu H, Schell MJ, Tsang TM, Teahan O, Zhou S, Califano JA, Jeoung NH, Harris RA, Verma A. Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. J Biol Chem 283: 22700‐22708, 2008.
 82.Meredith D, Christian HC. The SLC16 monocarboxylate transporter family. Xenobiotica 38: 1072‐1106, 2008.
 83.Merezhinskaya N, Fishbein WN, Davis JI, Foellmer JW. Mutations in MCT1 cDNA in patients with symptomatic deficiency in lactate transport. Muscle Nerve 23: 90‐97, 2000.
 84.Metzler‐Zebeli BU, Ganzle MG, Mosenthin R, Zijlstra RT. Oat β‐glucan and dietary calcium and phorphorus differentially modify intestinal expression of proinflammatory cytokines and monocarboxylate transporter 1 and cecal morphology in weaned pigs. J Nutr 142: 668‐674, 2012.
 85.Miyauchi S, Gopal E, Babu E, Srinivas SR, Kubo Y, Umapathy NS, Thakkar SV, Ganapathy V, Prasad PD. Sodium‐coupled electrogenic transport of pyroglutamate (5‐oxoproline) via SLC5A8, a monocarboxylate transporter. Biochim Biophys Acta 1798: 1164‐1171, 2010.
 86.Miyauchi S, Gopal E, Fei YJ, Ganapathy V. Functional identification of SLC5A8, a tumor suppressor down‐regulated in colon cancer, as a Na+‐coupled transport for short‐chain fatty acids. J Biol Chem 279: 13293‐13296, 2004.
 87.Nakamura T, Tsuchiya K, Watanabe M. Crosstalk between Wnt and Notch signaling in intestinal epithelial cell fate decision. J Gastroenterol 42: 705‐710, 2007.
 88.Nancolas B, Sessions RB, Halestrap AP. Identification of key binding site residues of MCT1 for AR‐C155858 reveals the molecular basis of its isoform selectivity. Biochem J 466: 177‐188, 2015.
 89.O'Keefe SJ. Diet, microorganisms and their metabolites, and colon cancer. Nat Rev Gastroenterol Hepatol 13: 691‐706, 2016.
 90.Otonkoski T, Jiao H, Kaminen‐Ahola N, Tapia‐Paez I, Ullah MS, Parton LE, Schuit F, Quintens R, Siplila I, Mayatepek E, Meissner T, Halestrap AP, Rutter GA, Kere J. Physical exercise‐induced hypoglycemia caused by failed silencing of monocarboxylate transporter 1 in pancreatic beta cells. Am J Hum Genet 81: 467‐474, 2007.
 91.Ovens MJ, Davies AJ, Wilson MC, Murray CM, Halestrap AP. AR‐C155858 is a potent inhibitor of monocarboxylate transporters MCT1 and MCT2 that binds to an intracellular site involving transmembrane helces 7‐10. Biochem J 425: 523‐530, 2010.
 92.Perez‐Escuredo J, Van Hee VF, Sboarina M, Falces J, Payen V, Pellerin L, Sonveaux P. Monocarboxylate transporters in the brain and in cancer. Biochim Biophys Acta 1863: 2481‐2497, 2016.
 93.Perz‐Escuredo J, Dadhich RK, Dhup S, Cacace A, Van Hee VF, De Saedeleer CJ, Sboarina M, Rodriguez F, Fontenille MJ, Brisson L, Porporato PE, Sonveaux P. Lactate promotes glutamine uptake and metabolism in oxidative cancer cells. Cell Cycle 15: 72‐83, 2016.
 94.Pinheiro C, Longatto‐Filho A, Azevedo‐Silva J, Casal M, Schmitt FC, Baltazar F. Role of monocarboxylate transporters in human cancers: State of the art. J Bioenerg Biomembr 44: 127‐139, 2012.
 95.Pinheiro C, Reis RM, Ricardo S, Longatto‐Filho A, Schmitt F, Baltazar F. Expression of monocarboxylate transporters 1, 2, and 4 in human tumours and their association with CD147 and CD44. J Biomed Biotechnol 2010: 427694, 2010.
 96.Polanski R, Hodgkinson CL, Fusi A, Nonaka D, Priest L, Kelly P, Trapani F, Bishop PW, White A, Critchlow SE, Smith PD, Blackhall F, Dive C, Morrow CJ. Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer. Clin Cancer Res 20: 926‐937, 2014.
 97.Ramakrishna BS. Role of the gut microbiota in human nutrition and metabolism. J Gastroenterol Hepatol 28(Suppl. 4): 9‐17, 2013.
 98.Reynolds DA, Rajendran VM, Binder HJ. Bicarbonate‐stimulated [14C]butyrate uptake in basolateral membrane vesicles of rat distal colon. Gastroenterology 105: 725‐732, 1993.
 99.Rios‐Covian D, Ruas‐Madiedo P, Margolles A, Gueimonde M, de Los Reyes‐Gavilan CG, Salazar N. Intestinal short chain fatty acids and their link with diet and human health. Front Microbiol 7: 185, 2016.
 100.Ritzhaupt A, Ellis A, Hosie KB, Shirazi‐Beechey SP. The characterization of butyrate transport across pig and human colonic luminal membrane. J Physiol 507: 819‐830, 1998.
 101.Ritzhaupt A, Wood IS, Ellis A, Hosie KB, Shirazi‐Beechey SP. Identification and characterization of a monocarboxylate transporter (MCT1) in pig and human colon: Its potential to transport L‐lactate as well as butyrate. J Physiol 513: 719‐732, 1998.
 102.Rodriguez AM, Perron B, Lacroix L, Caillou B, Leblanc G, Schlumberger M, Bidart JM, Pourcher T. Identification and characterization of a putative human iodide transporter located at the apical membrane of thyrocytes. J Clin Endocrinol Metab 87: 3500‐3503, 2002.
 103.Saksena S, Dwivedi A, Gill RK, Singla A, Alrefai WA, Malakooti J, Ramaswamy K, Dudeja PK. PKC‐dependent stimulation of the human MCT1 promoter involves transcription factor AP2. Am J Physiol Gastrointest Liver Physiol 296: G275‐G283, 2009.
 104.Saksena S, Theegala S, Bansal N, Gill RK, Tyagi S, Alrefai WA, Ramaswamy K, Dudeja PK. Mechanisms underlying modulation of monocarboxylate transporter 1 (MCT1) by somatostatin in human intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 297: G878‐G885, 2009.
 105.Schroder O, Opritz J, Stein J. Substrate and inhibitor specificity of butyrate uptake in apical membrane vesicles of the rat distal colon. Digestion 62: 152‐158, 2000.
 106.Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R, Shi H, Thangaraju M, Prasad PD, Maniccasamy S, Munn DH, Lee JR, Offermanns S, Ganapathy V. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40: 128‐139, 2014.
 107.Sivaprakasam S, Gurav A, Paschall AV, Coe GL, Chaudhary K, Cai Y, Kolhe R, Martin P, Browning D, Huang L, Shi H, Sifuentes H, Vijay‐Kumar M, Thompson SA, Munn DH, Mellor A, McGaha TL, Shiao P, Cutler CW, Liu K, Ganapathy V, Li H, Singh N. An essential role of Ffar2 (Gpr43) in dietary fibre‐mediated promotion of healthy composition of gut microbiota and suppression of intestinal carcinogenesis. Oncogenesis 5: e238, 2016.
 108.Sivaprakasam S, Prasad PD, Singh N. Benefits of short‐chain fatty acids and their receptors in inflammation and carcinogenesis. Pharmacol Ther 164: 144‐151, 2016.
 109.Soga T, Kamohara M, Takasaki J, Matsumoto S, Saito T, Ohishi T, Hiyama H, Matsuo A, Matsushime H, Furuichi K. Molecular identification of nicotinic acid receptor. Biochem Biophys Res Commun 303: 364‐369, 2003.
 110.Sprowl‐Tanio S, Habowski AN, Pate KT, McQuade MM, Wang K, Edwards RA, Grun F, Lyou Y, Waterman ML. Lactate/pyruvate transporter MCT‐1 is a direct Wnt target that confers sensitivity to 3‐bromopyruvate in colon cancer. Cancer Metab 4: 20, 2016.
 111.Srinivas SR, Gopal E, Zhuang L, Itagaki S, Martin PM, Fei YJ, Ganapathy V, Prasad PD. Cloning and functional identification of Slc5a12 as a sodium‐coupled low‐affinity transporter for monocarboxylates (SMCT2). Biochem J 392: 655‐664, 2005.
 112.Stacy AE, Jansson PJ, Richardson DR. Molecular pharmacology of ABCG2 and its role in chemoresistance. Mol Pharmacol 84: 655‐669, 2013.
 113.Stein J, Zores M, Schroder O. Short‐chain fatty acid (SCFA) uptake into Caco‐2 cells by a pH‐dependent and carrier mediated transport mechanism. Eur J Nutr 39: 121‐125, 2000.
 114.Tan J, McKenzie C, Potamitis M, Thorburn AN, Mackay CR, Macia L. The role of short‐chain fatty acids in health and disease. Adv Immunol 121: 91‐119, 2014.
 115.Tang H, Lu JY, Zheng X, Yang Y, Reagan JD. The psoriasis drug monomethylfumarate is a potent nicotinic acid receptor agonist. Biochem Biophys Res Commun 375: 562‐565, 2008.
 116.Tazoe H, Otomo Y, Kaji I, Tanaka R, Karaki SI, Kuwahara A. Roles of short‐chain fatty acids receptors, GPR41 and GPR43 on colonic functions. J Physiol Pharmacol 59(Suppl. 2): 251‐262, 2008.
 117.Thangaraju M, Ananth S, Martin PM, Roon P, Smith SB, Sterneck E, Prasad PD, Ganapathy V. c/ebpδ‐null mouse as a model for the double knockout of Slc5a8 and Slc5a12 in kidney. J Biol Chem 281: 26769‐26773, 2006.
 118.Thangaraju M, Carswell KN, Prasad PD, Ganapathy V. Colon cancer cells maintain low levels of pyruvate to avoid cell death caused by inhibition of HDAC1/HDAC3. Biochem J 417: 379‐389, 2009.
 119.Thangaraju M, Cresci GA, Itagaki S, Mellinger JD, Browning DD, Berger FG, Prasad PD, Ganapathy V. Sodium‐coupled transport of the short‐chain fatty acid butyrate by SLC5A8 and its relevance to colon cancer. J Gastrointest Surg 12: 1773‐1781, 2008.
 120.Thangaraju M, Cresci GA, Liu K, Ananth S, Gnanaprakasam JP, Browning DD, Mellinger JD, Smith SB, Digby GJ, Lambert NA, Prasad PD, Ganapathy V. GPR109A is a G‐protein‐coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res 69: 2826‐2832, 2009.
 121.Thangaraju M, Gopal E, Martin PM, Ananth S, Smith SB, Prasad PD, Sterneck E, Ganapathy V. SLC5A8 triggers tumor cell apoptosis through pyruvate‐dependent inhibition of histone deacetylases. Cancer Res 66: 11560‐11564, 2006.
 122.Thangaraju M, Karunakaran SK, Itagaki S, Gopal E, Elangovan S, Prasad PD, Ganapathy V. Transport by SLC5A8 with subsequent inhibition of histone deacetylase 1 (HDAC1) and HDAC3 underlies the antitumor activity of 3‐bromopyruvate. Cancer 115: 4655‐4666, 2009.
 123.Thibault R, Blachier F, Darcy‐Vrillon B, de Coppet P, Bourreille A, Segain JP. Butyrate utilization by the colonic mucosa in inflammatory bowel diseases: A transport deficiency. Inflamm Bowel Dis 16: 684‐695, 2010.
 124.Thibault R, de Coppet P, Daly K, Bourreille A, Cuff M, Bonnet C, Mosnier JF, Galmiche JP, Shirazi‐Beechey S, Segain JP. Down‐regulation of the monocarboxylate transporter 1 is involved in butyrate deficiency during intestinal inflammation. Gastroenterology 133: 1916‐1927, 2007.
 125.Thibault R. Blachier F, Darcy‐Vrillon B, de Coppet P, Bourreille A, Segain JP. Butyrate utilization by the colonic mucosa in inflammatory bowel diseases: A transport deficiency. Inflamm Bowel Dis 16: 684‐695, 2010.
 126.Tunaru S, Kero J, Schaub A, Wufka C, Blaukat A, Pfeffer K, Offermanns S. PUMA‐G and HM74 are receptors for nicotinic acid and mediate its anti‐lipolytic effect. Nat Med 9: 352‐355, 2003.
 127.Tyagi S, Venugopalakrishnan J, Ramaswamy K, Dudeja PK. Mechanism of n‐butyrate uptake in the human proximal colonic basolateral membranes. Am J Physiol Gastrointest Liver Physiol 282: G676‐G682, 2002.
 128.van Hasselt PM, Ferdinandusse S, Monroe GR, Ruiter JPN, Turkenburg M, Geerlings MJ, Duran K, Harakalova M, can der Zwaag B, Monavari AA, Okur I, Sharrard MJ, Cleary M, O'Connell N, Walker V, Rubio‐Gozalbo, ER, de Vries MC, Visser G, Houwen RHJ, van der Smagt JJ, Verhoeven‐Duif NM, Wanders RJA, van Haaften G. Monocarboxylate transporter 1 deficiency and ketone utilization. N Eng J Med 371: 1900‐1907, 2014.
 129.Vidyasagar S, Barmeyer C, Geibel J, Binder HJ, Rajendran VM. Role of short‐chain fatty acids in colonic HCO3− secretion. Am J Physiol Gastrointest Liver Physiol 288: G1217‐G1226, 2005.
 130.Villodre Tudela C, Boudry C, Stumpff F, Aschenbach JR, Vahjen W, Zentak J, Pieper R. Down‐regulation of monocarboxylate transporter 1 (MCT1) gene expression in the colon of piglets is linked to bacterial protein fermentation and pro‐inflammatory cytokine‐mediated signaling. Br J Nutr 113: 610‐617, 2015.
 131.Wang H, Yang C, Doherty JR, Roush WR, Cleveland JL, Bannister TD. Synthesis and structure‐activity relationships of pteridine dione and trione monocarboxylate transporter 1 inhibitors. J Med Chem 57: 7317‐7324, 2014.
 132.Wilson MC, Meredith D, Fox JE, Manoharan C, Davies AJ, Halestrap AP. Basigin (CD147) is the target for organomercurial inhibition of monocarboxylate transporter isoforms 1 and 4: The ancillary protein for the insensitive MCT2 is EMBIGIN (gp70). J Biol Chem 280: 27213‐27221, 2005.
 133.Wise A, Foord SM, Fraser NJ, Barnes AA, Elshourbagy N, Eilert M, Ignar DM, Murdock PR, Steplewski K, Green A, Brown AJ, Dowell SJ, Szekeres PG, Hassall DG, Marshall FH, Wilson S, Pike NB. Molecular identification of high and low affinity receptors for nicotinic acid. J Biol Chem 278: 9869‐9874, 2003.
 134.Wong JM, de Souza R, Kendall CW, Emam A, Jenkins DJ. Colonic health: Fermentation and short chain fatty acids. J Clin Gastroenterol 40: 235‐243, 2006.
 135.Wright EM. Glucose transporter families SLC5 and SLC50. Mol Aspects Med 34: 183‐196, 2013.
 136.Zhang Y, Bao YL, Wu Y, Yu CL, Sun Y, Li YX. Identification and characterization of the human SLC5A8 gene promoter. Cancer Genet Cytogenet 196: 124‐132, 2010.
 137.Ziegler K, Kerimi A, Poquet L, Williamson G. Butyric acid increases transepithelial transport of ferulic acid through upregulation of the monocarboxylate transporters SLC16A1 (MCT1) and SLC16A3 (MCT4). Arch Biochem Biophys 599: 3‐12, 2016.

 

Teaching Material

S. Sivaprakasam, Y. D. Bhutia, S. Yang, V. Ganapathy. Short-Chain Fatty Acid Transporters: Role in Colonic Homeostasis. Compr Physiol. 8: 2018, 299-314.

Didactic Synopsis

Major Teaching Points:

  • Fermentation of dietary fiber by colonic bacteria yields short-chain fatty acids (SCFA)
  • SCFA elicit beneficial effects on colon via extracellular and intracellular actions
  • Extracellular actions of SCFA occur via receptors in apical membrane of colonic epithelium
  • Intracellular actions of SCFA in colonic epithelium involve inhibition of histone deacetylases (HDACs), generation of energy, and conversion into ketone bodies
  • Entry of SCFA into colonic epithelium is mostly carrier-mediated
  • MCT1 and MCT4 are H+-coupled transporters expressed in apical membrane (MCT1) and basolateral membrane (MCT1 and MCT4) of colonic epithelium, mediating SCFA influx from lumen and SCFA efflux into blood
  • SMCT1 and SMCT2 are Na+-coupled transporters expressed solely in apical membrane of colonic epithelium, mediating SCFA influx from lumen
  • SCFA transporters are defective in ulcerative colitis
  • MCT1 and SMCT1 function as tumor suppressors in colon and are downregulated in colon cancer
  • The tumor-suppressive function of MCT1 and SMCT1 might be related to dietary fiber content

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.Figure 1–Figure 3

Figure 1. Teaching points: Cancer patients are stratified into two groups, low expressors of SLC16A1 and high expressors of SLC16A1, and the patients’ overall survival is plotted for the two groups. In patients with rectal cancer, there is a significant correlation between overall survival and the low or high expression of SLC16A1; high expressors show a better overall survival compared to low expressors. This correlation could be due to increased exposure of cancer cells in high expressors to luminal SCFA, which are tumor-suppressive. This significance is not seen in patients with colon cancer or when the data are combined for colon cancer patients and rectal cancer patients.

Figure 2. Teaching points: Cancer patients are stratified into two groups, low expressors of SLC5A8 and high expressors of SLC5A8, and the patients’ overall survival is plotted for the two groups. There is no significant correlation between the overall survival and the expression levels of SLC5A8 in patients with rectal cancer or when the data are combined for colon cancer patients and rectal cancer patients. There appears to be a significant correlation between the overall survival and the expression levels of SLC5A8 in patients with colon cancer. High expressors show less overall survival compared with low expressors. This correlation is opposite of what is expected for a tumor suppressor. We might need additional information on these patients such as dietary intake of fiber before making any conclusions based on the data.

Figure 3. Teaching points: The polarized distribution of the butyrate transporters is depicted in this figure. The H+-coupled transporter MCT1, the Na+-coupled transporter SMCT1, and the ATP-dependent exporter ABCG2 are expressed on the lumen-facing apical membrane of colonic epithelial cells. In contrast, MCT1 and MCT4, both are H+-coupled transporters, are expressed in the basolateral membrane of colonic epithelial cells. CD147 is a protein that has no transport function, but serves as a chaperone for MCT1 and MCT4; CD147 binds to the two transporters and facilitate their recruitment to the plasma membrane.

 


Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Short‐Chain Fatty Acid Transporters: Role in Colonic Homeostasis
 

How to Cite

Sathish Sivaprakasam, Yangzom D. Bhutia, Shengping Yang, Vadivel Ganapathy. Short‐Chain Fatty Acid Transporters: Role in Colonic Homeostasis. Compr Physiol 2017, 8: 299-314. doi: 10.1002/cphy.c170014