{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent studies have expanded our understanding of secretin’s (SCT) multifunctional roles in the gastrointestinal tract. In the gut, secretin is produced by enteroendocrine cells that coexpress several hormones, including CCK, GLP‐1, GIP, PYY, and neurotensin, highlighting its potential as a therapeutic target for metabolic diseases such as diabetes and obesity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Free fatty acid–induced signaling via CD36 on secretin‐positive cells further supports its role in fat digestion and homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Moreover, secretin modulates gastric motility through a vagally mediated pathway that involves presynaptic cholinergic neurons, VIP release, and a prostaglandin‐dependent cascade, while deficiency of secretin has been implicated in peptic ulcer disease due to reduced bicarbonate secretion and other protective mechanisms."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the liver, secretin exerts distinct effects on cholangiocyte physiology. In normal biliary epithelial cells, secretin acts as a mitogen; however, in cholangiocarcinoma cells its action is antiproliferative, suggesting that modulation of secretin receptor (SCTR) expression could offer therapeutic potential. In addition, the secretin/SCTR axis has been linked to mechanisms of biliary senescence and liver fibrosis in NAFLD/NASH."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSecretin also performs key functions in the central nervous system. Transient expression of secretin in serotonergic neurons during development, along with its localization in cerebellar Purkinje and basket cells, supports a neuromodulatory and trophic role in the human brain. Although rare genetic variants in the secretin gene have been explored in autism, secretin remains a candidate therapeutic agent for modulating neural activity. In addition, secretin signaling can enhance tyrosine hydroxylase transcription and catecholamine secretion via a cAMP–PKA–CREB pathway, further underscoring its neuromodulatory potential."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural and biophysical studies have provided further insights into secretin function. Cysteine‐trapping and molecular modeling approaches have delineated key contacts between secretin’s amino-terminal residues and the extracellular loops of its receptor, clarifying critical ligand–receptor docking interactions. Complementary work on lactam-constrained secretin analogues has not only improved binding affinity but also yielded competitive antagonists, while in vitro studies demonstrate that secretin self-assembles and undergoes a conformational switch from random coil to α-helical structure in the presence of phospholipids—features that may influence its bioactivity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRegulation of secretin gene expression is complex and involves multiple layers of control. Transcriptional regulation in secretin-expressing cells is governed in part by the balance between Sp1 and Sp3 binding and by the methylation status of a CpG island overlapping its promoter. Moreover, bile acids acting via the small heterodimer partner (SHP) can repress secretin gene expression, and a variable number of tandem repeats (VNTR) upstream of the gene may further modulate transcriptional efficiency. Retinoic acid signaling, through modulation of transcription factor phosphorylation via Cdk1, also contributes to secretin gene responsiveness."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, secretin has emerged as an influential modulator of energy balance. Elevation of circulating secretin levels following Roux-en-Y gastric bypass surgery correlates with brown adipose tissue activation and increased satiety, while exogenous administration of secretin in both mice and humans has been shown to reduce food intake. These findings support an important role for secretin in the gut–BAT–brain axis that may contribute to weight loss and metabolic improvements."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kristoffer L Egerod, Maja S Engelstoft, Kaare V Grunddal, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A major lineage of enteroendocrine cells coexpress CCK, secretin, GIP, GLP-1, PYY, and neurotensin but not somatostatin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocrinology (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/en.2012-1595"}], "href": "https://doi.org/10.1210/en.2012-1595"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23064014"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23064014"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Sinju Sundaresan, Rafiq Shahid, Terrence E Riehl, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CD36-dependent signaling mediates fatty acid-induced gut release of secretin and cholecystokinin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.12-217703"}], "href": "https://doi.org/10.1096/fj.12-217703"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23233532"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23233532"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Y Lu, C Owyang "}, {"type": "b", "children": [{"type": "t", "text": "Secretin-induced gastric relaxation is mediated by vasoactive intestinal polypeptide and prostaglandin pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurogastroenterol Motil (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1365-2982.2009.01271.x"}], "href": "https://doi.org/10.1111/j.1365-2982.2009.01271.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19239625"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19239625"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Jack W Love "}, {"type": "b", "children": [{"type": "t", "text": "Peptic ulceration may be a hormonal deficiency disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Med Hypotheses (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.mehy.2007.12.011"}], "href": "https://doi.org/10.1016/j.mehy.2007.12.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18280672"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18280672"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Paolo Onori, Candace Wise, Eugenio Gaudio, et al. 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