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progress and challenges, Nat Rev Endocrinol, 17, 162, 10.1038\u002Fs41574-020-00459-w\nSyed, 2018, Palmitic acid hydroxystearic acids activate GPR40, which is involved in their beneficial effects on glucose homeostasis, Cell Metab, 27, 419, 10.1016\u002Fj.cmet.2018.01.001\nPaschoal, 2020, Positive reinforcing mechanisms between GPR120 and PPARgamma modulate insulin sensitivity, Cell Metab, 31, 1173, 10.1016\u002Fj.cmet.2020.04.020\nKimura, 2020, Free fatty acid receptors in health and disease, Physiol Rev, 100, 171, 10.1152\u002Fphysrev.00041.2018\nTaylor, 2007, Hypoxia and gastrointestinal disease, J Mol Med (Berl), 85, 1295, 10.1007\u002Fs00109-007-0277-z\nFisher, 2013, Noninvasive monitoring of small intestinal oxygen in a rat model of chronic mesenteric ischemia, Cell Biochem Biophys, 67, 451, 10.1007\u002Fs12013-013-9611-y\nSinghal, 2020, Oxygen battle in the gut: hypoxia and hypoxia-inducible factors in metabolic and inflammatory responses in the intestine, J Biol Chem, 295, 10493, 10.1074\u002Fjbc.REV120.011188\nZheng, 2015, Physiologic hypoxia and oxygen homeostasis in the healthy intestine. A review in the theme: cellular responses to hypoxia, Am J Physiol Cell Physiol, 309, C350, 10.1152\u002Fajpcell.00191.2015\nZeitouni, 2016, The impact of hypoxia on intestinal epithelial cell functions: consequences for invasion by bacterial pathogens, Mol Cell Pediatr, 3, 14, 10.1186\u002Fs40348-016-0041-y\nGlover, 2016, Oxygen metabolism and barrier regulation in the intestinal mucosa, J Clin Invest, 126, 3680, 10.1172\u002FJCI84429\nSaeedi, 2015, HIF-dependent regulation of claudin-1 is central to intestinal epithelial tight junction integrity, Mol Biol Cell, 26, 2252, 10.1091\u002Fmbc.E14-07-1194\nKarhausen, 2004, Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis, J Clin Invest, 114, 1098, 10.1172\u002FJCI200421086\nSemenza, 2012, Hypoxia-inducible factors in physiology and medicine, Cell, 148, 399, 10.1016\u002Fj.cell.2012.01.021\nGonzalez, 2018, The role of hypoxia-inducible factors in metabolic diseases, Nat Rev Endocrinol, 15, 21, 10.1038\u002Fs41574-018-0096-z\nBodnaruc, 2016, Nutritional modulation of endogenous glucagon-like peptide-1 secretion: a review, Nutr Metab (Lond), 13, 92, 10.1186\u002Fs12986-016-0153-3\nMiyamoto, 2019, Gut microbiota confers host resistance to obesity by metabolizing dietary polyunsaturated fatty acids, Nat Commun, 10, 4007, 10.1038\u002Fs41467-019-11978-0\nRamakrishnan, 2016, Role of intestinal HIF-2alpha in health and disease, Annu Rev Physiol, 78, 301, 10.1146\u002Fannurev-physiol-021115-105202\nSinghal, 2021, HIF-2alpha activation potentiates oxidative cell death in colorectal cancers by increasing cellular iron, J Clin Invest, 131, 10.1172\u002FJCI143691\nXie, 2017, Activation of intestinal hypoxia-inducible factor 2alpha during obesity contributes to hepatic steatosis, Nat Med, 23, 1298, 10.1038\u002Fnm.4412\nSong, 2019, Gut-proglucagon-derived peptides are essential for regulating glucose homeostasis in mice, Cell Metab, 30, 976, 10.1016\u002Fj.cmet.2019.08.009\nDrucker, 2007, The role of gut hormones in glucose homeostasis, J Clin Invest, 117, 24, 10.1172\u002FJCI30076\nSvendsen, 2015, An analysis of cosecretion and coexpression of gut hormones from male rat proximal and distal small intestine, Endocrinology, 156, 847, 10.1210\u002Fen.2014-1710\nChristensen, 2016, Glucose-dependent insulinotropic polypeptide: effects on insulin and glucagon secretion in humans, Dan Med J, 63, B5230\nChan, 2016, Tuning the transcriptional response to hypoxia by inhibiting hypoxia-inducible factor (HIF) prolyl and asparaginyl hydroxylases, J Biol Chem, 291, 20661, 10.1074\u002Fjbc.M116.749291\nKeith, 2007, Hypoxia-inducible factors, stem cells, and cancer, Cell, 129, 465, 10.1016\u002Fj.cell.2007.04.019\nXiong, 2013, Activation of FFA1 mediates GLP-1 secretion in mice. 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2012, Esophageal cancer in Canada: trends according to morphology and anatomical location, Can J Gastroenterol, 26, 723, 10.1155\u002F2012\u002F649108\nThrift, 2012, The incidence of esophageal adenocarcinoma continues to rise: analysis of period and birth cohort effects on recent trends, Ann Oncol, 23, 3155, 10.1093\u002Fannonc\u002Fmds181\nNguyen, 2017, The annual risk of esophageal adenocarcinoma does not decrease over time in patients with Barrett's esophagus, Am J Gastroenterol, 112, 1049, 10.1038\u002Fajg.2017.18\nJemal, 2010, Cancer statistics, 2010, CA Cancer J Clin, 60, 277, 10.3322\u002Fcaac.20073\nWang, 2011, Residual embryonic cells as precursors of a Barrett's-like metaplasia, Cell, 145, 1023, 10.1016\u002Fj.cell.2011.05.026\nYamamoto, 2016, Mutational spectrum of Barrett's stem cells suggests paths to initiation of a precancerous lesion, Nat Commun, 7, 10380, 10.1038\u002Fncomms10380\nJiang, 2017, Transitional basal cells at the squamous-columnar junction generate Barrett's oesophagus, Nature, 550, 529, 10.1038\u002Fnature24269\nLiu, 2019, Etiology, cancer stem cells and potential diagnostic biomarkers for esophageal cancer, Cancer Lett, 458, 21, 10.1016\u002Fj.canlet.2019.05.018\nQue, 2019, Pathogenesis and cells of origin of Barrett's esophagus, Gastroenterology, 157, 349, 10.1053\u002Fj.gastro.2019.03.072\nAgoston, 2018, Columnar-lined esophagus develops via wound repair in a surgical model of reflux esophagitis, Cell Mol Gastroenterol Hepatol, 6, 389, 10.1016\u002Fj.jcmgh.2018.06.007\nWang, 2010, Aberrant epithelial-mesenchymal Hedgehog signaling characterizes Barrett's metaplasia, Gastroenterology, 138, 1810, 10.1053\u002Fj.gastro.2010.01.048\nZhang, 2019, Acidic bile salts induce epithelial to mesenchymal transition via VEGF signaling in non-neoplastic Barrett's cells, Gastroenterology, 156, 130, 10.1053\u002Fj.gastro.2018.09.046\nWilson, 2008, Prognostic significance of lymph node metastases and ratio in esophageal cancer, J Surg Res, 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10.1016\u002Fj.devcel.2010.12.014\nLiu, 2015, Confinement and low adhesion induce fast amoeboid migration of slow mesenchymal cells, Cell, 160, 659, 10.1016\u002Fj.cell.2015.01.007\nWolf, 2003, Compensation mechanism in tumor cell migration: mesenchymal-amoeboid transition after blocking of pericellular proteolysis, J Cell Biol, 160, 267, 10.1083\u002Fjcb.200209006\nPaul, 2017, Cancer cell motility: lessons from migration in confined spaces, Nat Rev Cancer, 17, 131, 10.1038\u002Fnrc.2016.123\nPankova, 2010, The molecular mechanisms of transition between mesenchymal and amoeboid invasiveness in tumor cells, Cell Mol Life Sci, 67, 63, 10.1007\u002Fs00018-009-0132-1\nBenoit, 2012, Complement protein C1q directs macrophage polarization and limits inflammasome activity during the uptake of apoptotic cells, J Immunol, 188, 5682, 10.4049\u002Fjimmunol.1103760\nClark, 2015, Modes of cancer cell invasion and the role of the microenvironment, Curr Opin Cell Biol, 36, 13, 10.1016\u002Fj.ceb.2015.06.004\nRohani, 2019, Acidification of tumor at stromal boundaries drives transcriptome alterations associated with aggressive phenotypes, Cancer Res, 79, 1952, 10.1158\u002F0008-5472.CAN-18-1604\nBrisson, 2012, pH regulators in invadosomal functioning: proton delivery for matrix tasting, Eur J Cell Biol, 91, 847, 10.1016\u002Fj.ejcb.2012.04.004\nParadise, 2013, Directional cell migration in an extracellular pH gradient: a model study with an engineered cell line and primary microvascular endothelial cells, Exp Cell Res, 319, 487, 10.1016\u002Fj.yexcr.2012.11.006\nRobey, 2009, Bicarbonate increases tumor pH and inhibits spontaneous metastases, Cancer Res, 69, 2260, 10.1158\u002F0008-5472.CAN-07-5575\nDuggan, 2018, siRNA library screening identifies a druggable immune-signature driving esophageal adenocarcinoma cell growth, Cell Mol Gastroenterol Hepatol, 5, 569, 10.1016\u002Fj.jcmgh.2018.01.012\nDuggan, 2006, Low pH induces co-ordinate regulation of gene expression in oesophageal cells, Carcinogenesis, 27, 319, 10.1093\u002Fcarcin\u002Fbgi211\nDuggan, 2016, The characterization of an intestine-like genomic signature maintained during Barrett's-associated adenocarcinogenesis reveals an NR5A2-mediated promotion of cancer cell survival, Sci Rep, 6, 32638, 10.1038\u002Fsrep32638\nDubiel, 2015, Diversity of COP9 signalosome structures and functional consequences, FEBS Lett, 589, 2507, 10.1016\u002Fj.febslet.2015.06.007\nChamovitz, 2009, Revisiting the COP9 signalosome as a transcriptional regulator, EMBO Rep, 10, 352, 10.1038\u002Fembor.2009.33\nDamsky, 2011, Beta-catenin signaling controls metastasis in Braf-activated Pten-deficient melanomas, Cancer Cell, 20, 741, 10.1016\u002Fj.ccr.2011.10.030\nQi, 2016, New Wnt\u002Fbeta-catenin target genes promote experimental metastasis and migration of colorectal cancer cells through different signals, Gut, 65, 1690, 10.1136\u002Fgutjnl-2014-307900\nBian, 2000, Nuclear accumulation of beta-catenin 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number of confirmed associations to 47, Nat Genet, 43, 246, 10.1038\u002Fng.764\nZhu, 2015, Nonsynonymous single nucleotide polymorphisms of NHE3 differentially decrease NHE3 transporter activity, Am J Physiol Cell Physiol, 308, C758, 10.1152\u002Fajpcell.00421.2014\nDas, 2018, The role of ion transporters in the pathophysiology of infectious diarrhea, Cell Mol Gastroenterol Hepatol, 6, 33, 10.1016\u002Fj.jcmgh.2018.02.009\nField, 2003, Intestinal ion transport and the pathophysiology of diarrhea, J Clin Invest, 111, 931, 10.1172\u002FJCI200318326\nZhao, 1999, Acute inhibition of Na\u002FH exchanger NHE-3 by cAMP: role of protein kinase a and NHE-3 phosphoserines 552 and 605, J Biol Chem, 274, 3978, 10.1074\u002Fjbc.274.7.3978\nHu, 2001, Dopamine acutely stimulates Na\u002FH exchanger (NHE3) endocytosis via clathrin-coated vesicles: dependence on protein kinase A-mediated NHE3 phosphorylation, J Biol Chem, 276, 26906, 10.1074\u002Fjbc.M011338200\nSingh, 2018, Cholera toxin inhibits SNX27-retromer-mediated delivery of cargo proteins to the plasma membrane, J Cell Sci, 131, jcs218610, 10.1242\u002Fjcs.218610\nChen, 2005, Enteropathogenic Escherichia coli: unravelling pathogenesis, FEMS Microbiol Rev, 29, 83, 10.1016\u002Fj.femsre.2004.07.002\nHodges, 2008, The enteropathogenic Escherichia coli effector protein EspF decreases sodium hydrogen exchanger 3 activity, Cell Microbiol, 10, 1735, 10.1111\u002Fj.1462-5822.2008.01163.x\nPiper, 2011, Endosomal transport via ubiquitination, Trends Cell Biol, 21, 647, 10.1016\u002Fj.tcb.2011.08.007\nNo, 2014, Unique regulation of human Na+\u002FH+ exchanger 3 (NHE3) by Nedd4-2 ligase that differs from non-primate NHE3s, J Biol Chem, 289, 18360, 10.1074\u002Fjbc.M113.541706\nYang, 2010, Nedd4 and Nedd4-2: closely related ubiquitin-protein ligases with distinct physiological functions, Cell Death Differ, 17, 68, 10.1038\u002Fcdd.2009.84\nArmando, 2014, Dopamine D3 receptor inhibits the ubiquitin-specific peptidase 48 to promote 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perinatal lethality in Nedd4-2-deficient mice, Nat Commun, 2, 287, 10.1038\u002Fncomms1284\nMalsure, 2014, Colon-specific deletion of epithelial sodium channel causes sodium loss and aldosterone resistance, J Am Soc Nephrol, 25, 1453, 10.1681\u002FASN.2013090936\nXue, 2020, An inducible intestinal epithelial cell-specific NHE3 knockout mouse model mimicking congenital sodium diarrhea, Clin Sci (Lond), 134, 941, 10.1042\u002FCS20200065\nZhou, 2007, Nedd4-2 catalyzes ubiquitination and degradation of cell surface ENaC, J Biol Chem, 282, 20207, 10.1074\u002Fjbc.M611329200\nHo, 2018, beta1Pix exchange factor stabilizes the ubiquitin ligase Nedd4-2 and plays a critical role in ENaC regulation by AMPK in kidney epithelial cells, J Biol Chem, 293, 11612, 10.1074\u002Fjbc.RA118.003082\nIsmail, 2014, The phosphorylation of endogenous Nedd4-2 in Na(+)-absorbing human airway epithelial cells, Eur J Pharmacol, 732, 32, 10.1016\u002Fj.ejphar.2014.03.005\nCrane, 1997, Activation of host cell protein 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Physiol, 293, F212, 10.1152\u002Fajprenal.00042.2007\nChow, 1999, The epithelial Na(+)\u002FH(+) exchanger, NHE3, is internalized through a clathrin-mediated pathway, J Biol Chem, 274, 37551, 10.1074\u002Fjbc.274.53.37551\nMayers, 2013, Regulation of ubiquitin-dependent cargo sorting by multiple endocytic adaptors at the plasma membrane, Proc Natl Acad Sci U S A, 110, 11857, 10.1073\u002Fpnas.1302918110\nPiper, 2014, Ubiquitin-dependent sorting in endocytosis, Cold Spring Harb Perspect Biol, 6, 10.1101\u002Fcshperspect.a016808\nSigismund, 2005, Clathrin-independent endocytosis of ubiquitinated cargos, Proc Natl Acad Sci U S A, 102, 2760, 10.1073\u002Fpnas.0409817102\nHenry, 2012, Regulation of endocytic clathrin dynamics by cargo ubiquitination, Dev Cell, 23, 519, 10.1016\u002Fj.devcel.2012.08.003\nWolfe, 2007, Ubiquitination differentially regulates clathrin-dependent internalization of protease-activated receptor-1, J Cell Biol, 177, 905, 10.1083\u002Fjcb.200610154\nTraub, 2007, 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2009, FGF15\u002FFGFR4 integrates growth factor signaling with hepatic bile acid metabolism and insulin action, J Biol Chem, 284, 11110, 10.1074\u002Fjbc.M808747200\nPotthoff, 2011, FGF15\u002F19 regulates hepatic glucose metabolism by inhibiting the CREB-PGC-1α pathway, Cell Metab, 13, 729, 10.1016\u002Fj.cmet.2011.03.019",{"EN":1859},"Modulation of Hepatic Protein Kinase Cβ Expression in Metabolic Adaptation to a Lithogenic 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