Glucagon-Like Peptide-1 and Its Receptor Agonist Exendin-4 Modulate Cholangiocyte Adaptive Response to Cholestasis
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Background & aims Cholangiopathies are characterized by progressive dysregulation of the balance between proliferation and death of cholangiocytes. In the course of cholestasis, cholangiocytes undergo a neuroendocrine transdifferentiation and their biology is regulated by neuroendocrine hormones. Glucagon-like peptide-1 (GLP-1), secreted by neuroendocrine cells, sustains beta-cell survival in experimental diabetes and induces the neuroendocrine transdifferentiation of pancreatic ductal cells. GLP-1 receptor (GLP-1R) selective agonist exendin-4 is used in humans as a novel therapeutic tool for diabetes. The aim of this study was to define if GLP-1 modulates cholangiocyte biologic response to cholestasis.Methods Expression of GLP-1R in cholangiocytes was determined. Effects on cholangiocyte proliferation of the in vitro and in vivo exposure to GLP-1 or exendin-4, together with the intracellular signals, were then studied. Synthesis of GLP-1 by cholangiocytes and the effects of GLP-1R blockage on their growth were also determined.Results Cholangiocytes express the GLP-1 receptor, which is up-regulated in the course of cholestasis. GLP-1 and exendin-4 increase cholangiocyte growth both in vitro and in vivo. The GLP-1R signal is mediated by the phosphatidyl-inositol-3-kinase, cAMP/Protein Kinase A, and Ca(2+)-CamKIIalpha but not by the ERK1/2 and PKCalpha pathways. Proliferating cholangiocytes synthesize GLP-1: neutralization of its action by GLP-1R antagonist blunts cholangiocyte response to cholestasis.Conclusions GLP-1 is required for the cholangiocyte adaptive response to cholestasis. Cholangiocytes are susceptible to the activation of GLP-1R and respond with increased proliferation and functional activity. Exendin-4 availability for employment in humans and these data may open novel perspectives for the medical treatment of cholangiopathies.
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Direct stimulation of the GLP-1 receptor on cholangiocytes can lead to enhanced cellular proliferation and an elevated likelihood of cholestasis.
“Further, direct stimulation of the GLP-1 receptor on cholangiocytes can lead to enhanced cellular proliferation and an elevated likelihood of cholestasis [47].”
From Exploring the Side Effects of GLP-1 Receptor Agonist: To Ensure Its Optimal Positioning (2025) · cites this paper as [47]
The ‘GLP-1R Activation Stimulates Cholangiocyte Proliferation In Vitro’ section reports increased rat cholangiocyte proliferation after GLP-1 or exendin-4 treatment. The Discussion describes GLP-1R activation as part of the cells’ adaptive response to existing cholestasis; it does not report an elevated likelihood of developing cholestasis. Page numbers were not provided in our copy. (LLM, conf=0.89)
Experimental — accuracy not yet measuredExperimental investigations have demonstrated that cholangiocytes are sensitive to GLP-1 and respond with augmented proliferation, potentially increasing the risk of duct obstruction.
“Experimental investigations have demonstrated that cholangiocytes are sensitive to GLP-1 and respond with augmented proliferation, potentially increasing the risk of duct obstruction [47,48].”
From Exploring the Side Effects of GLP-1 Receptor Agonist: To Ensure Its Optimal Positioning (2025) · cites this paper as [47]
The Discussion reports that cholangiocytes express the GLP-1 receptor, and the in vitro results show increased proliferation of rat cholangiocytes exposed to GLP-1. The paper does not report an increased risk of duct obstruction; its Discussion instead describes proliferation as part of the biliary tree’s repair response. Page numbers were not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredExendin-4 appears to stimulate cholangiocyte proliferation through the GLP-1 receptor, preventing cholangiocyte apoptosis in models of bile acid-induced damage and ductopenic cholangiopathies.
“exendin-4 appears to stimulate cholangiocyte proliferation through the GLP-1 receptor, hereby preventing cholangiocyte apoptosis in models of bile acid-induced damage and models of ductopenic cholangiopathies”
From Safety of Semaglutide (2021) · cites this paper as [96]
The GLP-1R Activation section reports that exendin-4 increased proliferation in normal and bile-duct-ligated rat cholangiocytes. But the Discussion says further studies are needed to assess effects on cholangiocyte apoptosis; the paper does not show that exendin-4 prevents apoptosis in models of bile acid-induced damage or ductopenic cholangiopathies. Page numbers are unavailable in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredGLP-1 has cholangioprotective effects against apoptosis and attenuating the reactive cholangiocyte phenotype.
“Apart from its metabolic effects, GLP-1 has also cholangioprotective effects against apoptosis and attenuating the reactive cholangiocyte phenotype.196 197”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [197]
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BackgroundSimon, T. G., Patorno, E., & Schneeweiss, S. (2022) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2021.07.010 · Cited by 98 · see citing works
Fuchs, C. D., Paumgartner, G., Mlitz, V., Kunczer, V., Halilbasic, E., Leditznig, N., Wahlström, A., Ståhlman, M., Thüringer, A., Kashofer, K., et al. (2018) · Gut · doi:10.1136/gutjnl-2017-314553 · Cited by 76 · see citing works
“6 In line, in our study small intestinal and colonic FXR mRNA and protein expression was reduced in Mdr2 −/− mice subjected to colesevelam feeding while at the same time colonic GLP-1 expression and portal blood levels of this hormone were increased (figures 5 and 7).”
BackgroundMasyuk, T. V., Masyuk, A. I., Pisarello, M. J. L., Howard, B. N., Huang, B. Q., Lee, P. Y., Fung, X., Sergienko, E. A., Ardecky, R., Chung, T. D. Y., et al. (2017) · Hepatology · doi:10.1002/hep.29284 · Cited by 77 · see citing works
“Although experimental evidence suggests that cholangiocytes express the receptor for GLP-1 and that its activation increases cell proliferation,((41)) further studies are needed to assess the role of GLP-1 in TGR5mediated cyst growth.”
Recent advances in the morphological and functional heterogeneity of the biliary epithelium
Han, Y., Glaser, S. S., Meng, F., Francis, H., Marzioni, M., McDaniel, K. M., Alvaro, D., Venter, J. K., Carpino, G., Onori, P., et al. (2013) · Experimental Biology and Medicine · doi:10.1177/1535370213489926 · Cited by 75 · see citing works
“Cholangiocytes express 17b-hydroxysteroid dehydrogenase 3 (17b-HSD3, the enzyme regulating testosterone synthesis) and secrete testosterone.52 Knock down of 17b-HSD3 reduces biliary proliferation.52 In vivo knockdown of a-CGRP decreases large biliary proliferation after BDL. BDL-induced large murine cholangiocyte prol…”
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Exendin-4, a glucagon-like peptide 1 receptor agonist, protects cholangiocytes from apoptosis
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“At the end of each procedure, the purity of the cholangiocytes was assessed by cytochemistry for c-glutamyltranspeptidase (c-GT).(9) 13 23 Cell viability at the end of the purification procedure was determined by trypan blue exclusion and was found to be .”
BackgroundMethodInfluentialSelf-citationZhang, Y., Wang, S., Chen, X., Wang, Z., Wang, X., Zhou, Q., Fang, W., & Zheng, C. (2022) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2022.111560 · Cited by 66 · see citing works
“Liraglutide, a human incretin GLP-1 analog, can achieve glycemic reduction without obvious glucose excursions (Meier, 2012).”
BackgroundAbrahami, D., Douros, A., Yin, H., Yu, O. H., Faillie, J., Montastruc, F., Platt, R. W., Bouganim, N., & Azoulay, L. (2018) · BMJ · doi:10.1136/bmj.k4880 · Cited by 65 · see citing works
Regulators of Cholangiocyte Proliferation
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“In particular, GLP1 can sustain the growth of cholangiocytes in a biliary damage model, in which it is synthesized and locally released by proliferating cholangiocytes to sustain their proliferation in an autocrine/paracrine manner [50].”
BackgroundCD26/DPP-4: Type 2 Diabetes Drug Target with Potential Influence on Cancer Biology
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Exploring the Side Effects of GLP-1 Receptor Agonist: To Ensure Its Optimal Positioning
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“Further, direct stimulation of the GLP-1 receptor on cholangiocytes can lead to enhanced cellular proliferation and an elevated likelihood of cholestasis [47].”
Animal models of cholestasis: An update on inflammatory cholangiopathies
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“GLP-1 regulates activated cholangiocytes and slows the progression of NASH toward cirrhosis [68,69].”
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“81 GLP-1 is required for the cholan-giocyte adaptive response to cholestasis and enhances the activity of cholangiocytes, 84 potentially supporting a direct effect.”
BackgroundRegulation of Biliary Proliferation by Neuroendocrine Factors
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“Another recent study has also shown that cholangiocytes are a major source of hepatic endothelin (ET)-1 production during the development of hepatopulmonary syndrome in cholestasis induced by BDL.97 Also, hepatopulmonary syndrome develops in biliary cirrhosis and is associated with increased plasma ET-1 and tumor necr…”
BackgroundInfluentialSelf-citationBiology of Cholangiocytes: From Bench to Bedside
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Self-citationWhen GLP-1 hits the liver: a novel approach for insulin resistance and NASH
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“Thus GLP-1 receptors are highly expressed on these cells, and GLP-1R activation blocks their Bax-induced mitochondrial apoptosis (15).”
BackgroundControl of Cholangiocyte Adaptive Responses by Visceral Hormones and Neuropeptides
Marzioni, M., Fava, G., Alvaro, D., Alpini, G. D., & Benedetti, A. (2008) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-008-8090-1 · Cited by 32 · see citing works
Self-citationUse of incretin-based drugs and risk of cholangiocarcinoma: Scandinavian cohort study
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“115 Among them, peroxisome proliferator-activated receptor α agonists, 116–121 farnesoid X receptor agonists, 122,123 and biotherapies such as anticluster of differentiation-20, 124,125 glucagon-like peptide-1 receptor agonists, 126,127 and estrogen-α receptor agonists 128 could be promising.”
Marzioni, M., Saccomanno, S., Agostinelli, L., Rychlicki, C., Minicis, S. D., Pierantonelli, I., Trauner, M. A., Fickert, P., Müller, T., Shanmukhappa, K. S., et al. (2012) · Journal of Hepatology · doi:10.1016/j.jhep.2012.11.033 · Cited by 27 · see citing works
“GLP-1R activation is a determinant of the proliferative responses of cholangiocytes to injury [15], as well as a major regulator of PDX-1 biological activity, in both the pancreas [7] and cholangiocytes [14].”
BackgroundMethodInfluentialSelf-citationGastrointestinal Motility Effects of GLP-1 Receptor Agonists
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“In rats, GLP-1 receptors are upregulated in cholangiocytes and promote cholan-giocyte proliferation in response to cholestasis, suggesting a reparatory role for GLP-1 in response to obstructive damage [49 ].”
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Bile acid signaling in MASLD: From pathogenesis to therapeutic applications
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“Glucagon-like peptide-1 and Its receptor agonist, exendin-4, stimulates biliary proliferation of both normal and cholestatic rodents (34).”
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A real‐world disproportionality analysis of semaglutide: Post‐marketing pharmacovigilance data
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“27 In light of this, it is imperative to further investigate whether GLP-1 RAs affect pancreatic cells through PI3K/AKT, ERK1/2, or other signaling pathways leading to the progression of pancreatitis with its associated carcinomas in the future.”
BackgroundClinical implications of novel aspects of biliary pathophysiology
Marzioni, M., Saccomanno, S., Candelaresi, C., Rychlicki, C., Agostinelli, L., Trozzi, L., Minicis, S. D., & Benedetti, A. (2010) · Digestive and Liver Disease · doi:10.1016/j.dld.2010.01.005 · Cited by 18 · see citing works
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Glucagon-like peptide 1 receptor agonists and cancer risk: the good, the bad and the unknown
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“GLP1 receptors are expressed by cholangiocytes, in which their stimulation enhances cell growth 42 .”
The Neglected Role of Bile Duct Epithelial Cells in NASH
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Finite volume simulation of calcium distribution in a cholangiocyte cell
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Cyclic AMP Signaling in Biliary Proliferation: A Possible Target for Cholangiocarcinoma Treatment?
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“With regard to gastrointestinal hormones, while secretin and GLP-1 stimulate biliary proliferation by enhancing cAMP machinery [10,53,54], others such as gastrin and somatostatin reduced biliary hyperplasia.”
BackgroundSelf-citationAutocrine regulation of biliary pathology by activated cholangiocytes
Jensen, K. J., Marzioni, M., Munshi, K., Afroze, S. H., Alpini, G. D., & Glaser, S. S. (2011) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00482.2011 · Cited by 12 · see citing works
“In BDL rats, GLP-1R was expressed by cholangiocytes and stimulation with GLP-1 activated the PI3K, cAMP-PKA, and Ca2 -CamKII pathways.”
BackgroundInfluentialSelf-citationGlucagon-like peptide-1 medicines and cancer
Yabut, J. M., & Drucker, D. J. (2026) · Nature Cancer · doi:10.1038/s43018-025-01110-1 · Cited by 11 · see citing works
“GLP-1R is not expressed in hepatocytes; however, Glp1r mRNA is detected in mouse intrahepatic T cells and endothelial cells and in cholangiocytes from bile duct-ligated rats 71,72 but not in hepatocellular carcinoma (HCC) cells 27 (Fig.”
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“19,20 These findings all provided strong evidence for the association between GLP-1 RA treatment and gallbladder and biliary disease adverse effect.”
BackgroundSun, H., & Qi, X. (2022) · Discover Oncology · doi:10.1007/s12672-022-00536-8 · Cited by 10 · see citing works
“1 3 cancer, but a higher risk of thyroid cancer [128].”
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“28 Biologic response of cholangiocytes to cholestasis could lead to pro-in fl ammatory secretions, subsequently developing gallbladder in fl ammation.”
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GLP-1 analogues: a new therapeutic approach to prevent ductopenia in cholangiopathies?
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Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis: A Narrative Review
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“Laboratory studies have demonstrated that cholangiocyte GLP-1 receptor activation leads to cellular proliferation [35–37].”
Cancer biology in diabetes update: Focusing on antidiabetic drugs
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“It was also reported that the elevated level of GLP-1 or GLP-1RA induces tumor proliferation and anti-apoptotic response in cholangiocytes 140 – 142 .”
BackgroundSignaling Pathways in Biliary Epithelial Cells
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“In addition, both in vitro and in vivo studies have speculated that activation and chronic over-stimulation of GLP-1RAs may increase the proliferation rate of cholangiocytes and lower the apoptosis rate [13,14].”
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Self-citationComparative Hepatic Outcomes of SGLT2i or DPP4i Compared to GLP‐1RA in CHB and T2DM Patients
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Therapeutic strategies, consequences and prospects of glucagon-like peptide-1 agonists
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Signaling pathways in biliary epithelial cells
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Obesity management medications for the surgeon
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GLP-1 AND CIRRHOSIS: EFFECTS ON MORTALITY AND LIVER-RELATED COMPLICATIONS
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“GLP–1RAs promote hepatic stellate cell quiescence, enhance lipid oxidation, suppress cholangiocyte apoptosis, and reduce inflammation, potentially influencing fibrosis and portal hypertension (26-28) .”
Approach to the Patient with Cholestasis and Jaundice
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“Proliferating cholangiocytes secrete angiogenic factors (e.g., vascular endothelial growth factor [VEGF], angiopoietins 1 and 2) that, in addition to paracrine signaling to the endothelium (hepatic artery neovascularization), are capable of autocrine stimulation of cholangiocyte proliferation [28, 45, 51 ].”
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Neuroendocrine Tumors of the Hepatobiliary Tract
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Glucagon-like peptide 1 receptor agonist: A potential game changer for cholangiocarcinoma
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АГОНІСТИ РЕЦЕПТОРІВ ГПП-1: ПЕРЕВАГИ ТА РИЗИКИ
Doroshkevych, I. O., Vlasenkо, М. V., Жамба, А. О., Semenenko, S., & Palamarchuk, A. V. (2026) · PROBLEMS OF ENDOCRINE PATHOLOGY · doi:10.21856/j-pep.2026.2.05
- Authors
- Marzioni, M., Alpini, G., Saccomanno, S., Candelaresi, C., Venter, J., Rychlicki, C., Fava, G., Francis, H., Trozzi, L., Glaser, S., & Benedetti, A.
- Affiliations
- Marche Polytechnic University (IT)
- Texas A&M University System (US)
- Corresponding author
- Marzioni, Marco
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2007-07
- Volume
- 133
- Issue
- 1
- Pages
- 244-255
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2032414382
- Semantic Scholar
- 04efd3fb15f679d81b1ef9e09796d0bf4bb319e7
- Cited by
- 96
- References
- 58
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 9 · 2023: 1 · 2022: 5 · 2021: 9 · 2020: 2 · 2019: 4 · 2018: 5 · 2017: 4 · 2016: 9 · 2015: 2 · 2014: 4 · 2013: 2 · 2012: 6
- FWCI
- 4.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion)
- Funders
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Università Politecnica delle Marche
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK062975, R01DK062975)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- glucagon-like peptide-1, exendin-4, GLP-1 receptor, cholangiocytes, cholestasis, cholangiopathy, cholangiocyte proliferation, neuroendocrine transdifferentiation, GLP-1 receptor signaling, phosphatidylinositol 3-kinase, GLP-1 receptor antagonists
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Exenatide, Adaptation, Physiological, Animals, Cholestasis, Extrahepatic, Bile Ducts, Cell Division, Hypoglycemic Agents, Male, Peptides, Rats, Inbred F344, Venoms, Signal Transduction, Up-Regulation, Receptors, Glucagon, Rats, Glucagon-Like Peptide 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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