Role of USF1 and USF2 as potential repressor proteins for human intestinal monocarboxylate transporter 1 promoter

Hadjiagapiou, Christos; Borthakur, Alip; Dahdal, Refka Y.; Gill, Ravinder K.; Malakooti, Jaleh; Ramaswamy, Krishnamurthy; Dudeja, Pradeep K.

doi:10.1152/ajpgi.00312.2004

Cited by 31 publications

(37 citation statements)

References 37 publications

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“…Butyrate anions are suggested to be primarily absorbed into the colonocytes by two distinct SCFA (18,34) and the Na ϩ -coupled SMCT1 (16,40). Our laboratory and others have extensively characterized the MCT1-mediated H ϩ -coupled butyrate transport and also the regulation of MCT1 in health and disease (1,7,9,17,35,36). Recent studies have shown that mucosal deficiency of butyrate during intestinal inflammation is secondary to downregulation of MCT1 expression and function (40).…”

Section: Discussionmentioning

confidence: 99%

“…Another transporter belonging to SLC5 solute-linked carrier family has recently been characterized as a Na ϩ -coupled transporter of butyrate and, therefore, known as sodium-coupled MCT1 (SMCT1) (16,40). Our laboratory's previous studies demonstrated the role of MCT1 in butyrate transport (18), its membrane localization along the length of the human intestine (15), and its transcriptional or posttranslational modulation by the transcription factor upstream stimulatory factor (17), butyrate (9), PKC- (35), somatostatin (36), and in response to enteropathogenic E. coli infection (7). With respect to MCT1 expression in disease, it has been shown that, during transition from normalcy to malignancy, MCT1 expression is downregulated in colonic tissues (24).…”

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confidence: 99%

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

Borthakur

Anbazhagan

Kumar

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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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.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

Borthakur

Anbazhagan

Kumar

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Nuclear extracts were prepared as described previously (12). Briefly, cells were washed twice with PBS and transferred to an Eppendorf tube.…”

Section: Methodsmentioning

confidence: 99%

Carrageenan induces interleukin-8 production through distinct Bcl10 pathway in normal human colonic epithelial cells

Borthakur

Bhattacharyya²,

Dudeja³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Borthakur A, Bhattacharyya S, Dudeja PK, Tobacman JK. Carrageenan induces interleukin-8 production through distinct Bcl10 pathway in normal human colonic epithelial cells. Am J Physiol Gastrointest Liver Physiol 292: G829 -G838, 2007. First published November 9, 2006; doi:10.1152/ajpgi.00380.2006.-Carrageenan is a high molecular weight sulfated polygalactan used to improve the texture of commercial food products. Its use increased markedly during the last half century, although carrageenan is known to induce inflammation in rheumatological models and in intestinal models of colitis. We performed studies to determine its direct effects on human intestinal cells, including normal human intestinal epithelial cells from colonic surgeries, the normal intestinal epithelial cell line NCM460, and normal rat ileal epithelial cells. Cells were treated with high molecular weight -carrageenan at a concentration of 1 g/ml for 1-96 h. IL-8, IL-8 promoter activity, total and nuclear NF-B, IB␣, phospho-IB␣, and Bcl10 were assessed by immunohistochemistry, Western blot, ELISA, and cDNA microarray. Increased Bcl10, nuclear and cytoplasmic NF-B, IL-8 promoter activation, and IL-8 secretion were detected following carrageenan exposure. Knockdown of Bcl10 by siRNA markedly reduced the increase in IL-8 that followed carrageenan exposure in the NCM460 cells. These results show, for the first time, that exposure of human intestinal epithelial cells to carrageenan triggers a distinct inflammatory pathway via activation of Bcl10 with NF-B activation and upregulation of IL-8 secretion. Since Bcl10 contains a caspase-recruitment domain, similar to that found in NOD2/CARD15 and associated with genetic predisposition to Crohn's disease, the study findings may represent a link between genetic and environmental etiologies of inflammatory bowel disease. Because of the high use of carrageenan as a food additive in the diet, the findings may have clinical significance. inflammation; colon; NF-B; IB␣ CARRAGEENANS ARE HIGH MOLECULAR weight sulfated polygalactans derived from several species of red seaweeds (Rhodophyceae). The most common forms of carrageenan (CGN) are lambda (), kappa (), and iota (). CGN has alternating disaccharide units composed of D-galactose-2-sulfate and D-galactose-2,6-disulfate. CGN is composed predominantly of alternating D-galactose-4-sulfate and 3,6-anhydro-D-galactose residues. CGN varies from CGN by sulfation of the 3,6-anhydro-D-galactose at the second carbon. Galactose residues are joined by ␣-1,3 and ␤-1,4 linkages. CGNs resemble to some extent the naturally occurring glycosaminoglycans owing to their backbone composition of sulfated disaccharides. CGNs are extracted from specific seaweeds, including Gigartina, Chondrus, and Eucheuma, and are used by the food industry to improve the texture of food products by acting to thicken, stabilize, or emulsify dairy products, salad dressings, infant formulas, processed meat, soy milk, and other food products (37,38). In addition to incorporation in foods, CGN has been used a...

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“…Although much is known with respect to the functional aspects of MCT1, very little is known regarding the mechanisms controlling MCT1 gene expression. In this regard, we and others have recently reported the cloning of the promoter region of the human MCT1 gene (11,18,19). The cloned fragment of MCT1 promoter (Ϫ871/ϩ91) was found to be highly active in Caco-2 cells (18) and colonic AA/C1 cells (10).…”

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confidence: 95%

“…In this regard, we and others have recently reported the cloning of the promoter region of the human MCT1 gene (11,18,19). The cloned fragment of MCT1 promoter (Ϫ871/ϩ91) was found to be highly active in Caco-2 cells (18) and colonic AA/C1 cells (10). The promoter has been shown to lack the TATA and CCAAT boxes and to have a long GC-rich area at its 3Ј end.…”

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confidence: 95%

PKC-dependent stimulation of the human MCT1 promoter involves transcription factor AP2

Saksena¹,

Dwivedi²,

Gill³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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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. First published November 25, 2008 doi:10.1152/ajpgi.90503.2008.-Monocarboxylate transporter (MCT1) plays an important role in the absorption of short-chain fatty acids (SCFA) such as butyrate in the human colon. Previous studies from our laboratory have demonstrated that phorbol ester, PMA (1 M, 24 h), upregulates butyrate transport and MCT1 protein expression in human intestinal Caco-2 cells. However, the molecular mechanisms involved in the transcriptional regulation of MCT1 gene expression by PMA in the intestine are not known. In the present study, we showed that PMA (0.1 M, 24 h) increased the MCT1 promoter activity (Ϫ871/ϩ91) by approximately fourfold. A corresponding increase in MCT1 mRNA abundance in response to PMA was also observed. PMA-induced stimulation of MCT1 promoter activity was observed as early as 1 h and persisted until 24 h, suggesting that the effects of PMA are attributable to initial PKC activation. Kinase inhibitor and phosphorylation studies indicated that these effects may be mediated through activation of the atypical PKC-isoform. 5Ј-deletion studies demonstrated that the MCT1 core promoter region (Ϫ229/ϩ91) is the PMA-responsive region. Site-directed mutagenesis studies showed the predominant involvement of potential activator protein 2 (AP2) binding site in the activation of MCT1 promoter activity by PMA. In addition, overexpression of AP2 in Caco-2 cells significantly increased MCT1 promoter activity in a dose-dependent manner. These findings showing the regulation of MCT1 promoter by PKC and AP2 are of significant importance for an understanding of the molecular regulation of SCFA absorption in the human intestine.short-chain fatty acid absorption; transcriptional regulation; human intestine; protein kinase C-; activator protein 2 MONOCARBOXYLATE TRANSPORTER 1 (MCT1) is a member of the solute carrier family1 of MCTs known to mediate the transport of monocarboxylates such as lactate and pyruvate (21, 46) and a wide range of short-chain fatty acids (SCFAs), e.g., acetate, propionate, and butyrate, across the plasma membrane of a variety of cell types (17,22,32). In humans, at least 14 MCT isoforms have been identified, but only MCT1-MCT4 have been structurally and functionally well characterized (21). Evidence suggests that SCFAs, particularly butyrate, serve as the principal metabolic fuel for colonic epithelial cells and exert a variety of effects fundamental to the health of normal colonic mucosa (47). For example, butyrate plays an essential role in suppressing mucosal inflammation (26, 34) and exhibits antitumorigenic effects such as induction of cell cycle arrest, differentiation, and apoptosis (20,23,40,57). Butyrate is also known to stimulate colonic electroneutral NaCl absorption and to inhibit Cl Ϫ secretion (2, 45). Although much is kn...

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Role of USF1 and USF2 as potential repressor proteins for human intestinal monocarboxylate transporter 1 promoter

Cited by 31 publications

References 37 publications

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

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

Carrageenan induces interleukin-8 production through distinct Bcl10 pathway in normal human colonic epithelial cells

PKC-dependent stimulation of the human MCT1 promoter involves transcription factor AP2

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