scholarly journals A novel nutrient sensing mechanism underlies substrate-induced regulation of monocarboxylate transporter-1

2012 ◽  
Vol 303 (10) ◽  
pp. G1126-G1133 ◽  
Author(s):  
Alip Borthakur ◽  
Shubha Priyamvada ◽  
Anoop Kumar ◽  
Arivarasu A. Natarajan ◽  
Ravinder K. Gill ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Apical Membrane ◽  
Nutrient Sensing ◽  
Monocarboxylate Transporter ◽  
Rat Colon ◽  
Intracellular Camp ◽  
Short Term ◽  
Monocarboxylate Transporter 1 ◽  
Sensing Mechanism ◽  
And Function

Monocarboxylate transporter isoform-1 (MCT1) plays an important role in the absorption of short-chain fatty acids (SCFAs) in the colon. Butyrate, a major SCFA, serves as the primary energy source for the colonic mucosa, maintains epithelial integrity, and ameliorates intestinal inflammation. Previous studies have shown substrate (butyrate)-induced upregulation of MCT1 expression and function via transcriptional mechanisms. The present studies provide evidence that short-term MCT1 regulation by substrates could be mediated via a novel nutrient sensing mechanism. Short-term regulation of MCT1 by butyrate was examined in vitro in human intestinal C2BBe1 and rat intestinal IEC-6 cells and ex vivo in rat intestinal mucosa. Effects of pectin feeding on MCT1, in vivo, were determined in rat model. Butyrate treatment (30–120 min) of C2BBe1 cells increased MCT1 function {p-(chloromercuri) benzene sulfonate (PCMBS)-sensitive [14C]butyrate uptake} in a pertussis toxin-sensitive manner. The effects were associated with decreased intracellular cAMP levels, increased Vmax of butyrate uptake, and GPR109A-dependent increase in apical membrane MCT1 level. Nicotinic acid, an agonist for the SCFA receptor GPR109A, also increased MCT1 function and decreased intracellular cAMP. Pectin feeding increased apical membrane MCT1 levels and nicotinate-induced transepithelial butyrate flux in rat colon. Our data provide strong evidence for substrate-induced enhancement of MCT1 surface expression and function via a novel nutrient sensing mechanism involving GPR109A as a SCFA sensor.

scholarly journals Mechanisms underlying modulation of monocarboxylate transporter 1 (MCT1) by somatostatin in human intestinal epithelial cells

2009 ◽  
Vol 297 (5) ◽  
pp. G878-G885 ◽  
Author(s):  
Seema Saksena ◽  
Saritha Theegala ◽  
Nikhil Bansal ◽  
Ravinder K. Gill ◽  
Sangeeta Tyagi ◽  
...  
Keyword(s):  
Map Kinase ◽  
Kinase Inhibitor ◽  
Apical Membrane ◽  
P38 Map Kinase ◽  
Monocarboxylate Transporter ◽  
Maximal Velocity ◽  
Dependent Manner ◽  
Intestinal Epithelial ◽  
Human Intestine ◽  
Monocarboxylate Transporter 1

Somatostatin (SST), an important neuropeptide of the gastrointestinal tract has been shown to stimulate sodium chloride absorption and inhibit chloride secretion in the intestine. However, the effects of SST on luminal butyrate absorption in the human intestine have not been investigated. Earlier studies from our group and others have shown that monocarboxylate transporter (MCT1) plays an important role in the transport of butyrate in the human intestine. The present studies were undertaken to examine the effects of SST on butyrate uptake utilizing postconfluent human intestinal epithelial Caco2 cells. Apical SST treatment of Caco-2 cells for 30–60 min significantly increased butyrate uptake in a dose-dependent manner with maximal increase at 50 nM (∼60%, P < 0.05). SST receptor 2 agonist, seglitide, mimicked the effects of SST on butyrate uptake. SST-mediated stimulation of butyrate uptake involved the p38 MAP kinase-dependent pathway. Kinetic studies demonstrated that SST increased the maximal velocity ( Vmax) of the transporter by approximately twofold without any change in apparent Michaelis-Menten constant ( Km). The higher butyrate uptake in response to SST was associated with an increase in the apical membrane levels of MCT1 protein parallel to a decrease in the intracellular MCT1 pool. MCT1 has been shown to interact specifically with CD147 glycoprotein/chaperone to facilitate proper expression and function of MCT1 at the cell surface. SST significantly enhanced the membrane levels of CD147 as well as its association with MCT1. This association was completely abolished by the specific p38 MAP kinase inhibitor, SB203580. Our findings demonstrate that increased MCT1 association with CD147 at the apical membrane in response to SST is p38 MAP kinase dependent and underlies the stimulatory effects of SST on butyrate uptake.

Short-term training increases human muscle MCT1 and femoral venous lactate in relation to muscle lactate

1998 ◽  
Vol 274 (1) ◽  
pp. E102-E107 ◽  
Author(s):  
A. Bonen ◽  
K. J. A. McCullagh ◽  
C. T. Putman ◽  
E. Hultman ◽  
N. L. Jones ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Vastus Lateralis ◽  
Venous Blood ◽  
Maximal Oxygen Consumption ◽  
Bicycle Ergometer ◽  
Monocarboxylate Transporter ◽  
Short Term ◽  
Bicycle Ergometry ◽  
Muscle Lactate ◽  
Monocarboxylate Transporter 1

We examined the effects of increasing a known lactate transporter protein, monocarboxylate transporter 1 (MCT1), on lactate extrusion from human skeletal muscle during exercise. Before and after short-term bicycle ergometry training [2 h/day, 7 days at 65% maximal oxygen consumption (V˙o 2 max)], subjects ( n = 7) completed a continuous bicycle ergometer ride at 30%V˙o 2 max (15 min), 60%V˙o 2 max (15 min), and 75% V˙o 2 max (15 min). Muscle biopsy samples (vastus lateralis) and arterial and femoral venous blood samples were obtained before exercise and at the end of each workload. After 7 days of training the MCT1 content in muscle was increased (+18%; P < 0.05). The concentrations of both muscle lactate and femoral venous lactate were reduced during exercise ( P < 0.05) that was performed after training. High correlations were observed between muscle lactate and venous lactate before training ( r = 0.92, P < 0.05) and after training ( r = 0.85, P < 0.05), but the slopes of the regression lines between these variables differed markedly. Before training, the slope was 0.12 ± 0.01 mM lactate ⋅ mmol lactate−1 ⋅ kg muscle dry wt−1, and this was increased by 33% after training to 0.18 ± 0.02 mM lactate ⋅ mmol lactate−1 ⋅ kg muscle dry wt−1. This indicated that after training the femoral venous lactate concentrations were increased for a given amount of muscle lactate. These results suggest that lactate extrusion from exercising muscles is increased after training, and this may be associated with the increase in skeletal muscle MCT1.

scholarly journals Monocarboxylate Transporter 1 (MCT1) mediates succinate export in the retina

2021 ◽  
Author(s):  
Celia M Bisbach ◽  
Daniel T Hass ◽  
James B Hurley
Keyword(s):  
Plasma Membranes ◽  
Ex Vivo ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Monocarboxylate Transporter ◽  
Gas Chromatography Mass Spectrometry ◽  
Short Term ◽  
Monocarboxylate Transporter 1 ◽  
Retinal Tissue ◽  
Ex Vivo Culture

Purpose: Succinate is exported by the retina and imported by eyecup tissue. The transporter(s) mediating this process have not yet been identified. Recent studies showed that Monocarboxylate Transporter 1 (MCT1) can transport succinate across plasma membranes in cardiac and skeletal muscle. Retina and retinal pigment epithelium (RPE) both express multiple MCT isoforms including MCT1. We tested the hypothesis that MCTs facilitate retinal succinate export and RPE succinate import. Methods: We assessed retinal succinate export and eyecup succinate import in short term ex vivo culture using gas chromatography-mass spectrometry. We test the dependence of succinate export and import on pH, proton ionophores, conventional MCT substrates, and the MCT inhibitors AZD3965, AR-C155858, and diclofenac. Results: Succinate exits retinal tissue through MCT1 but does not enter RPE through MCT1 or any other MCT. Intracellular succinate levels are a contributing factor that determines if an MCT1-expressing tissue will export succinate. Conclusions: MCT1 facilitates export of succinate from retinas. An unidentified, non-MCT transporter facilitates import of succinate into RPE.

Down-Regulation of the Monocarboxylate Transporter 1 Is Involved in Butyrate Deficiency During Intestinal Inflammation

2007 ◽  
Vol 133 (6) ◽  
pp. 1916-1927 ◽  
Author(s):  
Ronan Thibault ◽  
Pierre De Coppet ◽  
Kristian Daly ◽  
Arnaud Bourreille ◽  
Mark Cuff ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Monocarboxylate Transporter ◽  
Down Regulation ◽  
Monocarboxylate Transporter 1

miR-29a, b and c Regulate SLC5A8 Expression in Intestinal Epithelial Cells

2021 ◽  
Author(s):  
Arivarasu Natarajan Anbazhagan ◽  
Shubha Priyamvada ◽  
Anoop Kumar ◽  
Dulari Jayawardena ◽  
Alip Borthakur ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
In Silico Analysis ◽  
Short Chain Fatty Acids ◽  
Monocarboxylate Transporter ◽  
Luciferase Reporter ◽  
Intestinal Epithelial ◽  
Bacterial Fermentation ◽  
Monocarboxylate Transporter 1 ◽  
Beneficial Effects ◽  
And Function

Short chain fatty acids (SCFAs) produced by bacterial fermentation of dietary fiber exert myriad of beneficial effects including the amelioration of inflammation. SCFAs exist as anions at luminal pH, their entry into the cells depends on the expression and function of monocarboxylate transporters. In this regard, sodium-coupled monocarboxylate transporter-1 (SMCT-1) is one of the major proteins involved in the absorption of SCFA in the mammalian colon. However, very little is known about the mechanisms of regulation of SMCT-1 expression in health and disease. MicroRNAs (miRs) are known to play a key role in modulating gene expression. In silico analysis showed miR-29abc with highest context score and its binding region was conserved among mammals. The 3`-untranslated region (UTR) of human SMCT-1 gene was cloned into pmirGLO vector upstream of luciferase reporter and transiently transfected with miR-29a, b and c mimics into Caco-2 and/or T-84 cells. The presence of UTR of this gene significantly decreased luciferase activity compared to empty vector. Co-transfection with miR-29a, b or c resulted in further decrease in 3`UTR activity of SMCT-1 luciferase constructs. Mimic transfection significantly decreased SMCT-1 protein expression without altering mRNA expression. Further, the expression of miR-29a and c were significantly lower in mouse colon compared to small intestine, consistent with higher levels of SMCT-1 protein in the colon. Our studies demonstrated a novel finding in which miR-29a, b and c down-regulate SMCT-1 expression in colonic epithelial cells and may partly explain the differential expression of these transporters along the length of the GI tract.

scholarly journals The probiotic Lactobacillus plantarum counteracts TNF-α-induced downregulation of SMCT1 expression and function

2010 ◽  
Vol 299 (4) ◽  
pp. G928-G934 ◽  
Author(s):  
Alip Borthakur ◽  
Arivarasu N. Anbazhagan ◽  
Anoop Kumar ◽  
Geetu Raheja ◽  
Varsha Singh ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Promoter Activity ◽  
Monocarboxylate Transporter ◽  
Mucosal Inflammation ◽  
Lactobacillus Species ◽  
Inhibitory Effects ◽  
Monocarboxylate Transporter 1 ◽  
Tnf Α ◽  
Probiotic Lactobacillus ◽  
And Function

The major short-chain fatty acid (SCFA) butyrate is produced in the colonic lumen by bacterial fermentation of dietary fiber. Butyrate serves as primary fuel for the colonocytes and also ameliorates mucosal inflammation. Disturbed energy homeostasis seen in inflamed mucosa of inflammatory bowel disease patients has been attributed to impaired absorption of butyrate. Since sodium-coupled monocarboxylate transporter 1 (SMCT1, SLC5A8) has recently been shown to play a role in Na+-coupled transport of monocarboxylates, including SCFA, such as luminal butyrate, we examined the effects of proinflammatory TNF-α on SMCT1 expression and function and potential anti-inflammatory role of probiotic Lactobacillus species in counteracting the TNF-α effects. Rat intestinal epithelial cell (IEC)-6 or human intestinal Caco-2 cells were treated with TNF-α in the presence or absence of Lactobacilli culture supernatants (CS). TNF-α treatments for 24 h dose-dependently inhibited SMCT1-mediated, Na+-dependent butyrate uptake and SMCT1 mRNA expression in IEC-6 cells and SMCT1 promoter activity in Caco-2 cells. CS of L. plantarum (LP) stimulated Na+-dependent butyrate uptake (2.5-fold, P < 0.05), SMCT1 mRNA expression, and promoter activity. Furthermore, preincubating the cells with LP-CS followed by coincubation with TNF-α significantly attenuated the inhibitory effects of TNF-α on SMCT1 function, expression, and promoter activity. In vivo, oral administration of live LP enhanced SMCT1 mRNA expression in the colonic and ileal tissues of C57BL/6 mice after 24 h. Efficacy of LP or their secreted soluble factors to stimulate SMCT1 expression and function and to counteract the inhibitory effects of TNF-α on butyrate absorption could have potential therapeutic value.

scholarly journals Differential expression and function of monocarboxylate transporter 1 (MCT1) in human colon

2014 ◽  
Vol 12 ◽  
pp. S35
Author(s):  
Naomi Fearon ◽  
Elizabeth Ryan ◽  
Gavin Stewart ◽  
Des Winter ◽  
Alan Baird
Keyword(s):  
Differential Expression ◽  
Human Colon ◽  
Monocarboxylate Transporter ◽  
Monocarboxylate Transporter 1 ◽  
And Function

scholarly journals Lactobacillus acidophilus counteracts enteropathogenic E. coli-induced inhibition of butyrate uptake in intestinal epithelial cells

2015 ◽  
Vol 309 (7) ◽  
pp. G602-G607 ◽  
Author(s):  
Anoop Kumar ◽  
Waddah A. Alrefai ◽  
Alip Borthakur ◽  
Pradeep K. Dudeja
Keyword(s):  
Cell Surface ◽  
Intestinal Inflammation ◽  
Apical Cell ◽  
Monocarboxylate Transporter ◽  
Mucosal Inflammation ◽  
Intestinal Epithelial ◽  
Monocarboxylate Transporter 1 ◽  
E Coli ◽  
Fatty Acid Metabolite

Butyrate, a key short-chain fatty acid metabolite of colonic luminal bacterial action on dietary fiber, serves as a primary fuel for the colonocytes, ameliorates mucosal inflammation, and stimulates NaCl absorption. Absorption of butyrate into the colonocytes is essential for these intracellular effects. Monocarboxylate transporter 1 (MCT1) plays a major role in colonic luminal butyrate absorption. Previous studies (Tan J, McKenzie C, Potamitis M, Thorburn AN, Mackay CR, Macia L. Adv Immunol 121: 91–119, 2014.) showed decreased MCT1 expression and function in intestinal inflammation. We have previously shown (Borthakur A, Gill RK, Hodges K, Ramaswamy K, Hecht G, Dudeja PK. Am J Physiol Gastrointest Liver Physiol 290: G30–G35, 2006.) impaired butyrate absorption in human intestinal epithelial Caco-2 cells due to decreased MCT1 level at the apical cell surface following enteropathogenic E. coli (EPEC) infection. Current studies, therefore, examined the potential role of probiotic Lactobacilli in stimulating MCT1-mediated butyrate uptake and counteracting EPEC inhibition of MCT1 function. Of the five species of Lactobacilli, short-term (3 h) treatment with L. acidophilus (LA) significantly increased MCT1-mediated butyrate uptake in Caco-2 cells. Heat-killed LA was ineffective, whereas the conditioned culture supernatant of LA (LA-CS) was equally effective in stimulating MCT1 function, indicating that the effects are mediated by LA-secreted soluble factor(s). Furthermore, LA-CS increased apical membrane levels of MCT1 protein via decreasing its basal endocytosis, suggesting that LA-CS stimulation of butyrate uptake could be secondary to increased levels of MCT1 on the apical cell surface. LA-CS also attenuated EPEC inhibition of butyrate uptake and EPEC-mediated endocytosis of MCT1. Our studies highlight distinct role of specific LA-secreted molecules in modulating colonic butyrate absorption.

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