Leptin Transcriptionally Enhances Peptide Transporter (hPepT1) Expression and Activity via the cAMP-response Element-binding Protein and Cdx2 Transcription Factors

PepT1 is an intestinal epithelial apical membrane transporter that is expressed in the small intestine, with little or no expression in the normal colon. However, we previously demonstrated that colonic PepT1 may be expressed during chronic inflammation. To begin elucidating inflammatory hPepT1 signaling, we herein investigated the long term leptin treatments, on PepT1 expression and activity in Caco2-BBE cells, and began to reveal the involved signaling pathways. We successfully cloned the 723-bp hPepT1 promoter region and identified the human transcription initiation site 86 bp upstream from the translation start site. Leptin treatment dose- and time-dependently increased hPepT1 promoter and transport activities in Caco2-BBE cells, with maximal activity observed in cells treated with 100 nm leptin for 8 h. Under these conditions, we observed 2-fold increases in hPepT1 mRNA and protein expression, as well as increased transport activity. Our molecular analyses of possible signal-transduction pathways revealed that leptin treatment enhanced the intracellular levels of cAMP and phosphorylated cAMP-response element-binding protein (CREB) protein in Caco2-BBE cells, whereas our deletion, mutation, and CDX2 overexpression analyses demonstrated that interaction of the Cdx2 and phosphorylated CREB transcription factors was essential for leptin-induced hPepT1 transcription in Caco2-BBE cells. Our results indicate that leptin, which is increased in inflamed colonic mucosa, triggers colonic expression of hPepT1 via the CREB and Cdx2 transcription factors. These findings provide important new insights into the mechanisms of intestinal inflammation and may suggest new therapeutic modalities in the future. PepT1 is an intestinal epithelial apical membrane transporter that is expressed in the small intestine, with little or no expression in the normal colon. However, we previously demonstrated that colonic PepT1 may be expressed during chronic inflammation. To begin elucidating inflammatory hPepT1 signaling, we herein investigated the long term leptin treatments, on PepT1 expression and activity in Caco2-BBE cells, and began to reveal the involved signaling pathways. We successfully cloned the 723-bp hPepT1 promoter region and identified the human transcription initiation site 86 bp upstream from the translation start site. Leptin treatment dose- and time-dependently increased hPepT1 promoter and transport activities in Caco2-BBE cells, with maximal activity observed in cells treated with 100 nm leptin for 8 h. Under these conditions, we observed 2-fold increases in hPepT1 mRNA and protein expression, as well as increased transport activity. Our molecular analyses of possible signal-transduction pathways revealed that leptin treatment enhanced the intracellular levels of cAMP and phosphorylated cAMP-response element-binding protein (CREB) protein in Caco2-BBE cells, whereas our deletion, mutation, and CDX2 overexpression analyses demonstrated that interaction of the Cdx2 and phosphorylated CREB transcription factors was essential for leptin-induced hPepT1 transcription in Caco2-BBE cells. Our results indicate that leptin, which is increased in inflamed colonic mucosa, triggers colonic expression of hPepT1 via the CREB and Cdx2 transcription factors. These findings provide important new insights into the mechanisms of intestinal inflammation and may suggest new therapeutic modalities in the future. Gut epithelial cells absorb small dietary peptides via the action of apical membrane peptide transporters. A cDNA encoding an apical membrane protein accounting for this peptide transport capability has been cloned from humans and has been designated hPepT1 (1Adibi S.A. Gastroenterology. 1997; 113: 332-340Abstract Full Text PDF PubMed Scopus (289) Google Scholar, 2Adibi S.A. Am. J. Physiol. 2003; 285: G779-G788Crossref PubMed Scopus (184) Google Scholar, 3Daniel H. Annu. Rev. Physiol. 2004; 66: 361-384Crossref PubMed Scopus (452) Google Scholar, 4Daniel H. Kottra G. Pflugers Arch. 2004; 447: 610-618Crossref PubMed Scopus (389) Google Scholar, 5Fei Y.J. Ganapathy V. Leibach F.H. Prog. Nucleic Acids Res. Mol. Biol. 1998; 58: 239-261Crossref PubMed Scopus (77) Google Scholar, 6Meredith D. Boyd C.A.R. Cell Mol. Life Sci. 2000; 57: 754-778Crossref PubMed Scopus (100) Google Scholar, 7Liang R. Fei Y.J. Prasad P.D. Ramamoorthy S. Han H. Yang-Feng T.L. Hediger M.A. Ganapathy V. Leibach F.H. J. Biol. Chem. 1995; 270: 6456-6463Abstract Full Text Full Text PDF PubMed Scopus (479) Google Scholar). hPepT1 is an integral membrane-spanning protein expressed predominantly in the small intestine (8Ogihara H. Saito H. Shin B.C. Terado T. Takenoshita S. Nagamachi Y. Inui K. Takata K. Biochem. Biophys. Res. Commun. 1996; 220: 848-852Crossref PubMed Scopus (213) Google Scholar, 9Ogihara H. Suzuki T. Nagamachi Y. Inui K. Takata K. Histochem. J. 1999; 31: 169-174Crossref PubMed Scopus (105) Google Scholar), with additional expression recently reported in immune cells (10Charrier L. Driss A. Yan Y. Nduati V. Klapproth J.M. Sitaraman S. Merlin D. Lab. Invest. 2006; 86: 490-503Crossref PubMed Scopus (37) Google Scholar). hPepT1 is generally not expressed in the esophagus, stomach, or normal colon (8Ogihara H. Saito H. Shin B.C. Terado T. Takenoshita S. Nagamachi Y. Inui K. Takata K. Biochem. Biophys. Res. Commun. 1996; 220: 848-852Crossref PubMed Scopus (213) Google Scholar, 9Ogihara H. Suzuki T. Nagamachi Y. Inui K. Takata K. Histochem. J. 1999; 31: 169-174Crossref PubMed Scopus (105) Google Scholar, 11Merlin D. Si-Tahar M. Sitaraman S.V. Eastburn K. Williams I. Liu X. Hediger M.A. Madara J.L. Gastroenterology. 2001; 120: 1666-1679Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar); however, colonic hPepT1 expression has been observed in inflamed colon and inflammatory bowel disease (11Merlin D. Si-Tahar M. Sitaraman S.V. Eastburn K. Williams I. Liu X. Hediger M.A. Madara J.L. Gastroenterology. 2001; 120: 1666-1679Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar). It has been suggested that expression of hPepT1 in the inflamed colon could initiate uptake of small di-tri bacterial peptides, such as formyl-Met-Leu-Phe or muramyl dipeptide, which are abundantly present in the colonic lumen and have been associated with inflammation (11Merlin D. Si-Tahar M. Sitaraman S.V. Eastburn K. Williams I. Liu X. Hediger M.A. Madara J.L. Gastroenterology. 2001; 120: 1666-1679Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 12Merlin D. Steel A. Gewirtz A.T. Si-Tahar M. Hediger M.A. Madara J.L. J. Clin. Invest. 1998; 102: 2011-2018Crossref PubMed Scopus (87) Google Scholar, 13Vavricka S.R. Musch M.W. Chang J.E. Nakagawa Y. Phanvijhitsiri K. Waypa T.S. Merlin D. Schneewind O. Chang E.B. Gastroenterology. 2004; 127: 1401-1409Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar). The induction of hPepT1 expression in chronic colitis and in patients with short-bowel syndrome may indicate that specific inflammation-associated signaling pathways are activated (11Merlin D. Si-Tahar M. Sitaraman S.V. Eastburn K. Williams I. Liu X. Hediger M.A. Madara J.L. Gastroenterology. 2001; 120: 1666-1679Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 14Ziegler T.R. Fernandez-Estivariz C. Gu L.H. Bazargan N. Umeakunne K. Wallace T.M. Diaz E.E. Rosado K.E. Pascal R.R. Galloway J.R. Wilcox J.N. Leader L.M. Am. J. Clin. Nutr. 2002; 75: 922-930Crossref PubMed Scopus (159) Google Scholar). However, no previous study has directly investigated the activation of transcriptional activity of hPepT1. Leptin, which is the Y. R. M. M. L. J.M. PubMed Scopus Google Scholar), is an involved in of Y. R. 1995; PubMed Scopus Google Scholar, M.A. R. D. T. 1995; PubMed Scopus Google Scholar, L. S. 2000; PubMed Scopus Google via specific in the J.E. 1997; 66: PubMed Scopus Google Scholar). such as X. Am. J. Physiol. 1996; 270: Google Scholar), L. S. 2000; PubMed Scopus Google Scholar), and A. S. S. S. L. T. M. Y. 1998; PubMed Scopus Google Scholar), may leptin A. S. S. S. L. T. M. Y. 1998; PubMed Scopus Google Scholar, I. A. C. M. S. S. T. D. M. 2000; PubMed Scopus Google Scholar, I. M. H. N. D. A. Gastroenterology. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). 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E.E. 2001; PubMed Scopus Google Scholar). have investigated the possible of leptin in our demonstrated that leptin the activity of such as transporter M. Sitaraman S.V. Liu X. A. Merlin D. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), whereas study that leptin the increased and of of in V. Liu M.A. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). Leptin to the of cells was to the of the of and and the of and T. Liu M. Am. J. Physiol. 2001; PubMed Google Scholar). we previously demonstrated that term leptin treatment increased hPepT1 activity in and in M. S. A. T. G. Merlin D. M. C. A. J. Clin. Invest. 2001; PubMed Scopus Google Scholar). The region of the hPepT1 has been and into the of transcription have that the transcription in transcriptional of hPepT1 J. T. T. Inui K. Am. J. Physiol. Scopus Google Scholar). However, no previous study has investigated transcriptional of hPepT1 in to during intestinal inflammation. the present we investigated the molecular mechanisms the leptin-induced transcriptional activation of hPepT1 in the intestinal Cell cells and in with and cells in the in and and the was with with on from and of or Caco2-BBE cells in of and of the of the hPepT1 was from Caco2-BBE cells the The promoter of the hPepT1 was specific to the region of the human PepT1 and The of for of for for and for with for The was into the and promoter the hPepT1 promoter was with and and into the of cDNA of cDNA cAMP-response element-binding protein phosphorylated was with from Caco2-BBE cells and the to the was and to the The was human and the The of PepT1 was from this cDNA the hPepT1 and the The was with the hPepT1 and the The was into the and of the hPepT1 in the was with and and the was into the in the CREB and Cdx2 of the the with the hPepT1 promoter with and hPepT1 promoter with the Cdx2 site and hPepT1 promoter with the Cdx2 site and hPepT1 promoter with the Cdx2 site and The of for of for for and for with for The promoter of Cdx2 was specific and and of for of for for and for with for The was and into the for was with and into the promoter in new cells in for the cells and with of of encoding of the hPepT1 promoter and cells with the of the cells with and with the the Caco2-BBE cells with the of leptin or for or h. the activity of was with 100 of and the was for in activity was with to that of the in and for The observed activity reported in is expressed as the of the activity with to the in that The and are as in the of Cdx2 cells to on for and was was and of was with and with the cDNA The cDNA was with specific for Cdx2 and or and The of an for of for for and for with for The and The was the into the and the and Caco2-BBE cells with or the to the for in in cAMP cells and with 100 nm leptin or for the and cAMP levels from cAMP was with cells in for and for The was in an and the protein was for 100 in with with and on in of with The for and the to and was the and to the of of of and to and for The was in and for to the The was the and the protein was in with of and for the was and The for with in with and for with the The for with the and an for in with The for and the for the and of protein in for on or and to or for with in and for with or The for in and for with an The and with an The hPepT1 cDNA (11Merlin D. Si-Tahar M. Sitaraman S.V. Eastburn K. Williams I. Liu X. Hediger M.A. Madara J.L. Gastroenterology. 2001; 120: 1666-1679Abstract Full Text Full Text PDF PubMed Scopus (164) Google was as for Caco2-BBE cells with or 100 nm leptin for 8 and was the was for in and and on The to membrane Life and to The hPepT1 cDNA was with the and to the membrane in and of A was as the and was The on for with and in in the and in the apical The to in these for The apical was with with or or the was with or for the the cells the and was in The results are expressed as specific uptake of as of of in the of for the Cdx2 and Cdx2 are for the Cdx2 and Cdx2 are for the site The with the and with of and 100 nm of in for of was to the and of was to the and for The was the the of was in and of Caco2-BBE for the we of the we of Cdx2 and or on in to Cell The and the Nucleic and Cdx2 the Cell to the with Caco2-BBE cells to and treated with or leptin for 8 h. The cells with for initiate the with and in of for on The cells with of to the into to The and the was in and with protein to the The with or CREB The in protein for and with the and and in The was from the protein A and the treatment with for h. The was with for and with The Cdx2 (1Adibi S.A. Gastroenterology. 1997; 113: 332-340Abstract Full Text PDF PubMed Scopus (289) Google Scholar, 2Adibi S.A. Am. J. Physiol. 2003; 285: G779-G788Crossref PubMed Scopus (184) Google and Cdx2 H. Annu. Rev. Physiol. 2004; 66: 361-384Crossref PubMed Scopus (452) Google promoter in the specific and and and the and with reported as of and of the of the hPepT1 promoter region of the human PepT1 was specific to the region of the PepT1 revealed that this region was and The the previous J. T. T. Inui K. Am. J. Physiol. Scopus Google that the region to the transcription start site or was to the transcription start site in from human epithelial cells in our results for the that the hPepT1 transcription start site 86 bp upstream from the translation start site. with the revealed that the cloned promoter region for and in the and and in the for the and in the and and in the for transcription important for intestinal transcription and epithelial J.N. C. M. I. Biochem. Cell Biol. 1998; PubMed Scopus Google Scholar, Annu. Rev. Physiol. 1996; 58: PubMed Scopus Google Scholar), identified and in the and in the V. and D. for the protein identified and in the whereas site for cAMP element-binding protein (CREB) was of the transcription start site in the Leptin hPepT1 the of the hPepT1 promoter to leptin, hPepT1 into Caco2-BBE cells, to hPepT1 and leptin Caco2-BBE cells or with 100 nm leptin for and promoter activity was in of activity. Our results revealed that leptin treatment of Caco2-BBE dose- and time-dependently increased hPepT1 promoter with maximal of to 100 nm leptin A and Leptin in Caco2-BBE in of 100 nm to the apical and of Caco2-BBE increased uptake 8 and not or of leptin treatment with 100 nm leptin for 8 and leptin, with 100 nm leptin for and that treatment with leptin for 8 is with maximal of hPepT1 activity 100 nm leptin with 100 nm leptin of hPepT1 transport activity is leptin Caco2-BBE on or treated and with and nm leptin for 8 h. with an apical of whereas the of the was The and the cells and the intracellular was The results are expressed as specific uptake of of in and of leptin to the apical or increased uptake and leptin with 100 nm leptin with 100 nm we observed that the levels of hPepT1 in the membrane and in to 8 of leptin treatment on the and apical these results our conditions, leptin treatment to increased membrane hPepT1 protein expression and of transport Leptin hPepT1 mRNA and mRNA expression levels of hPepT1 of from Caco2-BBE that or treated with 100 nm leptin for 8 h. in and the the hPepT1 mRNA was increased in cells that leptin treatment increases hPepT1 expression the transcriptional The protein expression levels of hPepT1 on and membrane protein from Caco2-BBE that or treated with 100 nm leptin for 8 h. The and membrane of protein was and leptin treatment with cells and these results that 100 nm leptin for treatment increased of hPepT1 expression and to the with 100 nm leptin for 8 to hPepT1 promoter hPepT1 mRNA and protein and hPepT1 transport activity. The CREB for hPepT1 to possible pathways for leptin-induced hPepT1 We demonstrated that cAMP levels increased treatment of Caco2-BBE cells with 100 nm leptin, leptin with the increased intracellular cAMP with the revealed that CREB and present in Caco2-BBE cells and that levels increased leptin A and We to the of intracellular cAMP hPepT1 promoter activity via the CREB site. Our results revealed that in the CREB transcription site leptin-induced transcription the promoter in the of leptin and of 100 nm leptin, whereas the hPepT1 promoter activities of in the of leptin and in the of leptin that the the increased of hPepT1 promoter activity leptin in in the of leptin and of in the of leptin and these results suggest the that leptin treatment increases intracellular cAMP to activation of which the molecular cAMP and The of into the and to the of hPepT1 in Caco2-BBE cells. Caco2-BBE cells with or 100 nm leptin for of protein from on and to of and of from cells treated with or 100 nm The are expressed as of The of was in to the cells, and the of was to is for leptin-induced hPepT1 promoter activity. Caco2-BBE cells with the cloned hPepT1 region hPepT1 the cloned promoter with in the CREB site or the treated with or with 100 nm leptin for 8 and the activity was The to cells, as from of is for leptin-induced hPepT1 promoter activity. Caco2-BBE cells with the cloned hPepT1 region hPepT1 or the treated with or with 100 nm leptin in the or of the and for 8 and activity was The to cells, as from of The Cdx2 for hPepT1 promoter Cdx2 we Cdx2 is for leptin-induced hPepT1 promoter activity. We to to the Cdx2 for leptin-induced hPepT1 promoter activity. Our results revealed that of the Cdx2 leptin-induced increases in hPepT1 promoter activity that Cdx2 in hPepT1 transcription leptin, with 100 nm leptin, with We of the Cdx2 to which involved in the hPepT1 promoter in of the Cdx2 or the leptin-induced of hPepT1 promoter activity and whereas of the Cdx2 site no such for the in the To the of we cloned Cdx2 from Caco2-BBE cells, Caco2-BBE and leptin treatment increased hPepT1 promoter activity to in the Our results revealed that Caco2-BBE cells Cdx2 with the hPepT1 promoter have an enhanced hPepT1 to leptin with cells hPepT1 leptin, with 100 nm leptin, with 100 nm whereas with with Cdx2 hPepT1 promoter not cells hPepT1 8 leptin, 8 with 100 nm leptin, with 100 nm These results that Cdx2 is for hPepT1 promoter activity. We to the results in cells. in of the Cdx2 or leptin-induced hPepT1 promoter activity in Caco2-BBE cells, of the Cdx2 site no such these results suggest that the and Cdx2 are for leptin-induced increases of hPepT1 promoter of Cdx2 in Cdx2 is expressed in Caco2-BBE cells and is of protein activation and we cloned Cdx2 from Caco2-BBE cells and Caco2-BBE Caco2-BBE cells with Cdx2 and or with and to and the was with and and Caco2-BBE cells hPepT1 promoter activity Caco2-BBE cells or with and the hPepT1 promoter and the treated with 100 nm leptin or with for 8 and activity was The to cells observed in as from of treatment triggers an Cdx2 and Caco2-BBE cells or with and the hPepT1 promoter and or of the Cdx2 and and or and treated with 100 nm leptin or with for 8 and activity was The to cells observed in as from of Cdx2 and in Caco2-BBE to the possible interaction Cdx2 and phosphorylated CREB from Caco2-BBE cells Cdx2 with CREB and the with an the the Cdx2 no such of and Cdx2 was observed in Caco2-BBE cells Cdx2 or in Caco2-BBE with the These results suggest that leptin treatment of to interaction of and Cdx2 and of hPepT1 To the of Cdx2 and for activation of the hPepT1 leptin we and to to Cdx2 with as of protein from or with the with of or and for the in and and The and of in from and Caco2-BBE cells and and and revealed that of the from and with Cdx2 the in an and results and of the from not for with the in an and These results suggest that Cdx2 and with Cdx2 and to the activation of hPepT1 promoter activity leptin To this we or Caco2-BBE and with or CREB The with specific to or of the Cdx2 Our results revealed in cells, CREB not to the Cdx2 in cells, CREB and to Cdx2 These results suggest that the interaction and Cdx2 is important for leptin-induced hPepT1 promoter activity. We previously reported that hPepT1 is expressed in the inflamed colon of inflammatory bowel disease patients (11Merlin D. Si-Tahar M. Sitaraman S.V. Eastburn K. Williams I. Liu X. Hediger M.A. Madara J.L. Gastroenterology. 2001; 120: 1666-1679Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar). It is that colonic hPepT1 expression may initiate the inflammatory bacterial such as formyl-Met-Leu-Phe and muramyl D. Steel A. Gewirtz A.T. Si-Tahar M. Hediger M.A. Madara J.L. J. Clin. Invest. 1998; 102: 2011-2018Crossref PubMed Scopus (87) Google Scholar, 13Vavricka S.R. Musch M.W. Chang J.E. Nakagawa Y. Phanvijhitsiri K. Waypa T.S. Merlin D. Schneewind O. Chang E.B. Gastroenterology. 2004; 127: 1401-1409Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar). However, no previous has to the mechanisms hPepT1 expression in the colon. an to our of hPepT1 expression in colonic and inflammatory bowel we herein to and the leptin-induced hPepT1 Leptin has been to transport in and in Caco2-BBE cells in in the of hPepT1 from intracellular to the apical membrane M. S. A. T. G. Merlin D. M. C. A. J. Clin. Invest. 2001; PubMed Scopus Google Scholar). of leptin was observed in the small intestine, PepT1 is expressed in the apical membrane of cells M. S. A. T. G. Merlin D. M. C. A. J. Clin. Invest. 2001; PubMed Scopus Google Scholar). However, the present findings suggest that leptin may transcription of the encoding hPepT1. the present we demonstrated that long term leptin treatment increased hPepT1 protein expression and the associated hPepT1 transport activity in Caco2-BBE cells. The of leptin on the hPepT1 promoter and transport activities cells treated for with We could that signaling on hPepT1 expression could these was observed of leptin was to the apical or membrane of the Caco2-BBE which with the previous that term leptin treatment the apical not enhanced hPepT1 transport in Caco2-BBE M. S. A. T. G. Merlin D. M. C. A. J. Clin. Invest. 2001; PubMed Scopus Google Scholar). these suggest that and long term leptin hPepT1 activity via mechanisms in Caco2-BBE cells. Our present results indicate that the long term is in to transcription of the encoding hPepT1. The leptin in our study is However, additional of leptin in inflamed colonic epithelial cells S. Liu X. L. Gu L.H. T.R. Gewirtz A. Merlin D. J. 2004; PubMed Scopus Google could provide of leptin and colonic has previously been with with that the has the and uptake of leptin, the and S. C. J. 1998; PubMed Scopus Google Scholar). the of action of the long term leptin with leptin of 100 to that in our have been to have such as increased in cells from human cells and to uptake in cells R. S.R. S. G. M. Res. 2001; PubMed Scopus Google Scholar, G. J. S. D. R. A. 2001; PubMed Scopus Google Scholar). factors could to the increased of hPepT1 transcription associated with intestinal inflammation in our results important of leptin for hPepT1 transport activity in colonic epithelial cells in intestinal inflammation. an to the signaling pathways this transcriptional we cloned and the region of the hPepT1 in Caco2-BBE cells. The identified promoter region was to the previously cloned from human J. T. T. Inui K. Am. J. Physiol. Scopus Google and not or We to the transcription initiation site of the human hPepT1 for the and identified transcription initiation site 86 bp upstream from the The transcription start of the and PepT1 have been and bp upstream of the start T. K. H. H. Y. K. I. A. Gastroenterology. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, Y.J. M. Liu Ganapathy V. Ganapathy Leibach F.H. Biophys. 2000; PubMed Scopus Google Scholar), that the transcriptional start promoter of the hPepT1 promoter region identified CREB site from the transcription start that cAMP CREB may be involved in of hPepT1 have that leptin treatment intracellular cAMP levels in leptin and and cAMP in cells Am. J. Physiol. 1999; Scholar). the present we that leptin treatment enhanced the activity of the CREB from the region of the hPepT1 not that of the CREB that an CREB site is for leptin-induced hPepT1 promoter activity. our results revealed that the or of the CREB site not to the transcriptional activity of hPepT1 in Caco2-BBE cells, that CREB may be to small of the possible CREB are cAMP X. G. J. H. R. S. J.R. T. M. Sci. S. A. 102: PubMed Scopus Google Scholar, J.R. PubMed Scopus Google Scholar). the of additional CREB for promoter protein as for transcriptional activation CREB S. 2000; Google Scholar). The are involved in the of such as intestinal and the transport protein S.A. Am. J. Physiol. 2003; 285: G779-G788Crossref PubMed Scopus (184) Google Scholar, 7Liang R. Fei Y.J. Prasad P.D. Ramamoorthy S. Han H. Yang-Feng T.L. Hediger M.A. Ganapathy V. Leibach F.H. J. Biol. Chem. 1995; 270: 6456-6463Abstract Full Text Full Text PDF PubMed Scopus (479) Google Scholar, M. S. A. T. G. Merlin D. M. C. A. J. Clin. Invest. 2001; PubMed Scopus Google Scholar, J. T. T. Inui K. Am. J. Physiol. Scopus Google Scholar, S. 2000; Google Scholar). Cdx2 to in and H. K. H. H. H. H. N. K. K. K. J. Biol. PubMed Scopus Google Scholar), and was recently demonstrated that the of are to intestinal mucosa, and PepT1 expression H. K. H. H. H. H. N. K. K. K. J. Biol. PubMed Scopus Google Scholar). our promoter identified Cdx2 to that Cdx2 be involved in leptin-induced hPepT1 revealed that overexpression of Cdx2 in Caco2-BBE enhanced leptin-induced hPepT1 promoter activity that this was in hPepT1 promoter the Cdx2 the Cdx2 and to leptin-induced hPepT1 promoter whereas the Cdx2 site to the CREB not hPepT1 promoter activity. We CREB and Cdx2 to with during leptin-induced transcription of hPepT1. Our results revealed that protein levels increased leptin and and Cdx2 could be from Caco2-BBE cells not from Caco2-BBE cells. with the and analyses revealed that with the Cdx2 leptin on our we herein that the of leptin in inflamed colonic S. Liu X. L. Gu L.H. T.R. Gewirtz A. Merlin D. J. 2004; PubMed Scopus Google could to of leptin in with Our results suggest that the of leptin in increased intracellular cAMP in the colonic epithelial cells, intracellular protein signaling such as the to the of CREB and which is increased expression of hPepT1 and enhanced uptake of the small di-tri bacterial that intestinal inflammation L. Merlin D. Lab. Invest. 2006; 86: Full Text Full Text PDF PubMed Scopus Google Scholar). These findings provide important new insights into intestinal inflammation and may to new therapeutic modalities in the future.