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Regulation of Biliary Proliferation by Neuroendocrine Factors

2011; Elsevier BV; Volume: 178; Issue: 2 Linguagem: Inglês

10.1016/j.ajpath.2010.09.043

1525-2191

Md. Kamruzzaman Munshi, Sally Priester, Eugenio Gaudio, Fuquan Yang, Gianfranco Alpini, Romina Mancinelli, Candace Wise, Fanyn Meng, Antonio Franchitto, Paolo Onori, Shannon Glaser,

Genetics and Neurodevelopmental Disorders

The proliferation of cholangiocytes occurs during the progression of cholestatic liver diseases and is critical for the maintenance and/or restoration of biliary mass during bile duct damage. The ability of cholangiocytes to proliferate is important in many different human pathologic conditions. Recent studies have brought to light the concept that proliferating cholangiocytes serve as a unique neuroendocrine compartment in the liver. During extrahepatic cholestasis and other pathologic conditions that trigger ductular reaction, proliferating cholangiocytes acquire a neuroendocrine phenotype. Cholangiocytes have the capacity to secrete and respond to a variety of hormones, neuropeptides, and neurotransmitters, regulating their surrounding cell functions and proliferative activity. In this review, we discuss the regulation of cholangiocyte growth by neuroendocrine factors in animal models of cholestasis and liver injury, which includes a discussion of the acquisition of neuroendocrine phenotypes by proliferating cholangiocytes and how this relates to cholangiopathies. We also review what is currently known about the neuroendocrine phenotypes of cholangiocytes in human cholestatic liver diseases (ie, cholangiopathies) that are characterized by ductular reaction. The proliferation of cholangiocytes occurs during the progression of cholestatic liver diseases and is critical for the maintenance and/or restoration of biliary mass during bile duct damage. The ability of cholangiocytes to proliferate is important in many different human pathologic conditions. Recent studies have brought to light the concept that proliferating cholangiocytes serve as a unique neuroendocrine compartment in the liver. During extrahepatic cholestasis and other pathologic conditions that trigger ductular reaction, proliferating cholangiocytes acquire a neuroendocrine phenotype. Cholangiocytes have the capacity to secrete and respond to a variety of hormones, neuropeptides, and neurotransmitters, regulating their surrounding cell functions and proliferative activity. In this review, we discuss the regulation of cholangiocyte growth by neuroendocrine factors in animal models of cholestasis and liver injury, which includes a discussion of the acquisition of neuroendocrine phenotypes by proliferating cholangiocytes and how this relates to cholangiopathies. We also review what is currently known about the neuroendocrine phenotypes of cholangiocytes in human cholestatic liver diseases (ie, cholangiopathies) that are characterized by ductular reaction. The liver is formed by two types of epithelia: hepatocytes (which account for 70% of the nucleated liver population) and intrahepatic bile duct epithelial cells or cholangiocytes (which account for 3% to 5% of the endogenous liver cells).1Alpini G. Prall R.T. LaRusso N.F. The pathobiology of biliary epithelia. The Liver: Biology & Pathobiology, ed 4, ch 29.in: Arias I.M. Boyer J.L. Chisari F.V. Fausto N. Jakoby W. Schachter D. Shafritz D.A. Lippincott Williams & Wilkins, Philadelphia2001: pp 421-435Google Scholar, 2Alpini G. Lenzi R. Sarkozi L. Tavoloni N. Biliary physiology in rats with bile ductular cell hyperplasia: evidence for a secretory function of proliferated bile ductules.J Clin Invest. 1988; 81: 569-578Crossref PubMed Scopus (286) Google Scholar Cholangiocytes line the intrahepatic and extrahepatic bile ducts of the liver and participate in several cellular processes, including the modification of the bile of canalicular origin2Alpini G. Lenzi R. Sarkozi L. Tavoloni N. Biliary physiology in rats with bile ductular cell hyperplasia: evidence for a secretory function of proliferated bile ductules.J Clin Invest. 1988; 81: 569-578Crossref PubMed Scopus (286) Google Scholar during transit through the biliary system before it reaches the duodenum and the detoxification of xenobiotics.1Alpini G. Prall R.T. LaRusso N.F. The pathobiology of biliary epithelia. The Liver: Biology & Pathobiology, ed 4, ch 29.in: Arias I.M. Boyer J.L. Chisari F.V. Fausto N. Jakoby W. Schachter D. Shafritz D.A. Lippincott Williams & Wilkins, Philadelphia2001: pp 421-435Google Scholar, 2Alpini G. Lenzi R. Sarkozi L. Tavoloni N. Biliary physiology in rats with bile ductular cell hyperplasia: evidence for a secretory function of proliferated bile ductules.J Clin Invest. 1988; 81: 569-578Crossref PubMed Scopus (286) Google Scholar, 3LeSage G. Glaser S. Marucci L. Benedetti A. Phinizy J.L. Rodgers R. Caligiuri A. Papa E. Tretjak Z. Jezequel A.M. Holcomb L.A. Alpini G. Acute carbon tetrachloride feeding induces damage of large but not small cholangiocytes from BDL rat liver.Am J Physiol Gastrointest Liver Physiol. 1999; 276: G1289-G1301PubMed Google Scholar, 4Glaser S. Gaudio E. Miller T. Alvaro D. Alpini G. Cholangiocyte proliferation and liver fibrosis.Expert Rev Mol Med. 2009; 11: e7Crossref PubMed Scopus (140) Google Scholar The secretion of ductal bicarbonate is coordinately regulated by a variety of stimulatory or inhibitory factors, including gastrointestinal hormones (eg, secretin, somatostatin, and bombesin), neuropeptides, and neurotransmitters.5Kanno N. LeSage G. Glaser S. Alpini G. Regulation of cholangiocyte bicarbonate secretion.Am J Physiol Gastrointest Liver Physiol. 2001; 281: G612-G625PubMed Google Scholar Among these factors, secretin and its basolateral receptors (SR; expressed only by cholangiocytes in the liver)6Alpini G. Ulrich II, C.D. Phillips J.O. Pham L.D. Miller L.J. LaRusso N.F. Upregulation of secretin receptor gene expression in rat cholangiocytes after bile duct ligation.Am J Physiol Gastrointest Liver Physiol. 1994; 266: G922-G928Google Scholar are the major players in the regulation of bicarbonate secretion.5Kanno N. LeSage G. Glaser S. Alpini G. Regulation of cholangiocyte bicarbonate secretion.Am J Physiol Gastrointest Liver Physiol. 2001; 281: G612-G625PubMed Google Scholar Secretin binds to SR, stimulating intracellular cAMP levels and inducing the phosphorylation of protein kinase A (PKA).7Glaser S. Alvaro D. Roskams T. Phinizy J.L. Stoica G. Francis H. Ueno Y. Barbaro B. Marzioni M. Mauldin J. Rashid S. Mancino M.G. LeSage G. Alpini G. Dopaminergic inhibition of secretin-stimulated choleresis by increased PKC-γ expression and decrease of PKA activity.Am J Physiol Gastrointest Liver Physiol. 2003; 284: G683-G694PubMed Google Scholar Subsequently, PKA phosphorylation induces the activation of cystic fibrosis transmembrane conductance regulator (CFTR), leading to the secretion of Cl− at the apical membrane of cholangiocytes, resulting in membrane depolarization.8Alpini G. Ulrich C. Roberts S. Phillips J.O. Ueno Y. Podila P.V. Colegio O. LeSage G. Miller L.J. LaRusso N.F. Molecular and functional heterogeneity of cholangiocytes from rat liver after bile duct ligation.Am J Physiol Gastrointest Liver Physiol. 1997; 272: G289-G297Google Scholar The Cl− efflux from CFTR creates a Cl− gradient that induces activation of the apically located Cl−/HCO3− anion exchanger 2 (AE2),9LeSage G. Glaser S. Gubba S. Robertson W.E. Phinizy J.L. Lasater J. Rodgers R.E. Alpini G. Regrowth of the rat biliary tree after 70% partial hepatectomy is coupled to increased secretin-induced ductal secretion.Gastroenterology. 1996; 111: 1633-1644Abstract Full Text PDF PubMed Scopus (121) Google Scholar, 10Banales J.M. Arenas F. Rodriguez-Ortigosa C.M. Saez E. Uriarte I. Doctor R.B. Prieto J. Medina J.F. Bicarbonate-rich choleresis induced by secretin in normal rat is taurocholate-dependent and involves AE2 anion exchanger.Hepatology. 2006; 43: 266-275Crossref PubMed Scopus (73) Google Scholar which results in secretin-stimulated bicarbonate-enriched bile.2Alpini G. Lenzi R. Sarkozi L. Tavoloni N. Biliary physiology in rats with bile ductular cell hyperplasia: evidence for a secretory function of proliferated bile ductules.J Clin Invest. 1988; 81: 569-578Crossref PubMed Scopus (286) Google Scholar Signaling through SR plays a key role in the regulation of biliary growth/damage (see Secretin, Somatostatin, and cAMP-Dependent Signaling). Cholangiocytes are the target cells in a variety of animal models of cholestasis (see Animal Models and in Vitro Systems) and human cholangiopathies.1Alpini G. Prall R.T. LaRusso N.F. The pathobiology of biliary epithelia. The Liver: Biology & Pathobiology, ed 4, ch 29.in: Arias I.M. Boyer J.L. Chisari F.V. Fausto N. Jakoby W. Schachter D. Shafritz D.A. Lippincott Williams & Wilkins, Philadelphia2001: pp 421-435Google Scholar, 11Alvaro D. Mancino M.G. Glaser S. Gaudio E. Marzioni M. Francis H. Alpini G. Proliferating cholangiocytes: a neuroendocrine compartment in the diseased liver.Gastroenterology. 2007; 132: 415-431Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar Proliferation of cholangiocytes is critical for maintenance of the homeostasis of the biliary tree and for secretory function during the pathogenesis of chronic cholestatic liver diseases, such as primary biliary cirrhosis (PBC), and primary sclerosing cholangitis.1Alpini G. Prall R.T. LaRusso N.F. The pathobiology of biliary epithelia. The Liver: Biology & Pathobiology, ed 4, ch 29.in: Arias I.M. Boyer J.L. Chisari F.V. Fausto N. Jakoby W. Schachter D. Shafritz D.A. Lippincott Williams & Wilkins, Philadelphia2001: pp 421-435Google Scholar Interest in understanding the neuroendocrine nature of biliary proliferation has increased in the past several years with the identification of several neuroendocrine factors regulating the homeostasis of the biliary tree by autocrine and paracrine mechanisms in animal models of cholestasis11Alvaro D. Mancino M.G. Glaser S. Gaudio E. Marzioni M. Francis H. Alpini G. Proliferating cholangiocytes: a neuroendocrine compartment in the diseased liver.Gastroenterology. 2007; 132: 415-431Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar and in human cholangiopathies.1Alpini G. Prall R.T. LaRusso N.F. The pathobiology of biliary epithelia. The Liver: Biology & Pathobiology, ed 4, ch 29.in: Arias I.M. Boyer J.L. Chisari F.V. Fausto N. Jakoby W. Schachter D. Shafritz D.A. Lippincott Williams & Wilkins, Philadelphia2001: pp 421-435Google Scholar In addition, cholangiocytes display neuroendocrine phenotypes (such as chromogranin A, glycolipid A2-B4, S-100 protein, neural cell adhesion molecule, and the addition of neuroendocrine granules) during the progression of human cholestatic liver diseases.11Alvaro D. Mancino M.G. Glaser S. Gaudio E. Marzioni M. Francis H. Alpini G. Proliferating cholangiocytes: a neuroendocrine compartment in the diseased liver.Gastroenterology. 2007; 132: 415-431Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 12Roskams T. van den Oord J.J. De Vos R. Desmet V.J. Neuroendocrine features of reactive bile ductules in cholestatic liver disease.Am J Pathol. 1990; 137: 1019-1025PubMed Google Scholar The number of factors that participate in the regulation of cholangiocyte proliferation has quickly expanded in the past several years. These neuroendocrine factors affecting the function and proliferation of cholangiocytes are thoroughly discussed in this review, and key factors are highlighted in Table 1, Table 2. Several previous reviews have highlighted the role of neuroendocrine factors in the regulation of biliary proliferation.4Glaser S. Gaudio E. Miller T. Alvaro D. Alpini G. Cholangiocyte proliferation and liver fibrosis.Expert Rev Mol Med. 2009; 11: e7Crossref PubMed Scopus (140) Google Scholar, 5Kanno N. LeSage G. Glaser S. Alpini G. Regulation of cholangiocyte bicarbonate secretion.Am J Physiol Gastrointest Liver Physiol. 2001; 281: G612-G625PubMed Google Scholar, 11Alvaro D. Mancino M.G. Glaser S. Gaudio E. Marzioni M. Francis H. Alpini G. Proliferating cholangiocytes: a neuroendocrine compartment in the diseased liver.Gastroenterology. 2007; 132: 415-431Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, 52Kanno N. LeSage G. Glaser S. Alvaro D. Alpini G. Functional heterogeneity of the intrahepatic biliary epithelium.Hepatology. 2000; 31: 555-561Crossref PubMed Scopus (109) Google Scholar However, owing to the rapid expansion of the list of factors that affect biliary proliferation, these reviews are not current and comprehensive. Although a variety of studies have emphasized the importance of proliferating cholangiocytes in the development of fibrosis, this topic is not discussed in this review.Table 1Neurotransmitters and Neuromodulators That Affect Cholangiocyte Proliferation and FunctionNeurotransmitter/neuromodulatorStructureReceptorsEffect on proliferation/functionReferencesMet-enkephalinDelta, mu, and kappa ORsIncrease in opioid synthesis during cholestasis limits excessive cholangiocyte proliferation via delta OR13Marzioni M. Alpini G. Saccomanno S. de Minicis S. Glaser S. Francis H. Trozzi L. Venter J. Orlando F. Fava G. Candelaresi C. Macarri G. Benedetti A. Endogenous opioids modulate the growth of the biliary tree in the course of cholestasis.Gastroenterology. 2006; 130: 1831-1847Abstract Full Text Full Text PDF PubMed Scopus (41) Google ScholarSerotonin 5-hydroxytryptamineSerotonin 1A and 1B receptorsAutocrine loop based on serotonin secretion that limits the growth of the biliary tree during chronic cholestasis14Marzioni M. Glaser S. Francis H. Marucci L. Benedetti A. Alvaro D. Taffetani S. Ueno Y. Roskams T. Phinizy J.L. Venter J. Fava G. LeSage G. Alpini G. Autocrine/paracrine regulation of the growth of the biliary tree by the neuroendocrine hormone serotonin.Gastroenterology. 2005; 128: 121-137Abstract Full Text Full Text PDF PubMed Scopus (100) Google ScholarEpinephrine/norepinephrineβ1-ARβ2-ARRequired for cholangiocyte proliferation in response to BDL15LeSage G. Alvaro D. Glaser S. Francis H. Marucci L. Roskams T. Phinizy J.L. Marzioni M. Benedetti A. Taffetani S. Barbaro B. Fava G. Ueno Y. Alpini G. Alpha-1 adrenergic receptor agonists modulate ductal secretion of BDL rats via Ca(2+)- and PKC-dependent stimulation of cAMP.Hepatology. 2004; 40: 1116-1127Crossref PubMed Scopus (53) Google Scholar, 16Francis H. LeSage G. DeMorrow S. Alvaro D. Ueno Y. Venter J. Glaser S. Mancino M.G. Marucci L. Benedetti A. Alpini G. The α2-adrenergic receptor agonist UK 14,304 inhibits secretin-stimulated ductal secretion by downregulation of the cAMP system in bile duct-ligated rats.Am J Physiol Cell Physiol. 2007; 293: C1252-C1262Crossref PubMed Scopus (24) Google Scholar, 17Glaser S. Alvaro D. Francis H. Ueno Y. Marucci L. Benedetti A. De Morrow S. Marzioni M. Mancino M.G. Phinizy J.L. Reichenbach R. Fava G. Summers R. Venter J. Alpini G. Adrenergic receptor agonists prevent bile duct injury induced by adrenergic denervation by increased cAMP levels and activation of Akt.Am J Physiol Gastrointest Liver Physiol. 2006; 290: G813-G826Crossref PubMed Scopus (49) Google Scholar, 18Marzioni M. Ueno Y. Glaser S. Francis H. Benedetti A. Alvaro D. Venter J. Fava G. Alpini G. Cytoprotective effects of taurocholic acid feeding on the biliary tree after adrenergic denervation of the liver.Liver Int. 2007; 27: 558-568Crossref PubMed Scopus (23) Google Scholarα1-ARα2-ARRegulation of secretin-stimulated ductal secretionAcetylcholineM3-AChEnhances the effect of secretin; required for cholangiocyte proliferation in response to BDL; maintains biliary mass19LeSage G. Alvaro D. Benedetti A. Glaser S. Marucci L. Baiocchi L. Eisel W. Caligiuri A. Phinizy J.L. Rodgers R. Francis H. Alpini G. Cholinergic system modulates growth, apoptosis, and secretion of cholangiocytes from bile duct-ligated rats.Gastroenterology. 1999; 117: 191-199Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 20Alvaro D. Alpini G. Jezequel A.M. Bassotti C. Francia C. Fraioli F. Romeo R. Marucci L. Le Sage G. Glaser S. Benedetti A. Role and mechanisms of action of acetylcholine in the regulation of rat cholangiocyte secretory functions.J Clin Invest. 1997; 100: 1349-1362Crossref PubMed Scopus (114) Google Scholar, 21Marzioni M. Francis H. Benedetti A. Ueno Y. Fava G. Venter J. Reichenbach R. Mancino M.G. Summers R. Alpini G. Glaser S. Ca2+-dependent cytoprotective effects of ursodeoxycholic and tauroursodeoxycholic acid on the biliary epithelium in a rat model of cholestasis and loss of bile ducts.Am J Pathol. 2006; 168: 398-409Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 22Marzioni M. LeSage G. Glaser S. Patel T. Marienfeld C. Ueno Y. Francis H. Alvaro D. Tadlock L. Benedetti A. Marucci L. Baiocchi L. Phinizy J.L. Alpini G. Taurocholate prevents the loss of intrahepatic bile ducts due to vagotomy in bile duct-ligated rats.Am J Physiol Gastrointest Liver Physiol. 2003; 284: G837-G852PubMed Google ScholarGABAGABAA, GABAB, GABAC receptorsAfter damage of large bile ducts by GABA, small ducts replenish the biliary tree by amplification of Ca2+-dependent signaling and de novo acquisition of large secretory phenotypes23Mancinelli R. Franchitto A. Gaudio E. Onori P. Glaser S. Francis H. Venter J. Demorrow S. Carpino G. Kopriva S. White M. Fava G. Alvaro D. Alpini G. After damage of large bile ducts by γ-aminobutyric acid, small ducts replenish the biliary tree by amplification of calcium-dependent signaling and de novo acquisition of large cholangiocyte phenotypes.Am J Pathol. 2010; 176: 1790-1800Abstract Full Text Full Text PDF PubMed Scopus (56) Google ScholarAnandamideCb1, VR1Anandamide inhibits cholangiocyte during BDL via activation of thioredoxin 1/redox factor 1 and AP-1 activation24DeMorrow S. Francis H. Gaudio E. Ueno Y. Venter J. Onori P. Franchitto A. Vaculin B. Vaculin S. Alpini G. Anandamide inhibits cholangiocyte hyperplastic proliferation via activation of thioredoxin 1/redox factor 1 and AP-1 activation.Am J Physiol Gastrointest Liver Physiol. 2008; 294: G506-G519Crossref PubMed Scopus (49) Google ScholarHistamineH1R, H3RH3R agonist RAMH inhibits biliary growth of BDL rats; small mouse cholangiocytes proliferate in response to H1R stimulation25Francis H. Glaser S. Demorrow S. Gaudio E. Ueno Y. Venter J. Dostal D. Onori P. Franchitto A. Marzioni M. Vaculin S. Vaculin B. Katki K. Stutes M. Savage J. Alpini G. Small mouse cholangiocytes proliferate in response to H1 histamine receptor stimulation by activation of the IP3/CaMK I/CREB pathway.Am J Physiol Cell Physiol. 2008; 295: C499-C513Crossref PubMed Scopus (109) Google Scholar, 26Francis H. Franchitto A. Ueno Y. Glaser S. DeMorrow S. Venter J. Gaudio E. Alvaro D. Fava G. Marzioni M. Vaculin B. Alpini G. H3 histamine receptor agonist inhibits biliary growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2/ELK-1 pathway.Lab Invest. 2007; 87: 473-487PubMed Google ScholarAP-1, activator protein-1; AR, androgen receptor; OR, opiod receptor; RAMH, R-α-methylhistamine dihydrobromide. Open table in a new tab Table 2Peptide Hormones and Other Neuroendocrine Factors That Affect Cholangiocyte Proliferation and FunctionHormoneReceptorsEffect on proliferationReferencesCGRP (α/β)CLR, RAMP1, RCPStimulates an increase in biliary mass; lack of CGRP reduces biliary proliferation in response to BDL27Glaser S. Ueno Y. DeMorrow S. Chiasson V.L. Katki K.A. Venter J. Francis H.L. Dickerson I.M. DiPette D.J. Supowit S.C. Alpini G. Knockout of α-calcitonin gene-related peptide reduces cholangiocyte proliferation in bile duct ligated mice.Lab Invest. 2007; 87: 914-926Crossref PubMed Scopus (35) Google ScholarEstrogenER-α/ER-βStimulates cholangiocyte proliferation28Alvaro D. Alpini G. Onori P. Franchitto A. Glaser S. Le Sage G. Gigliozzi A. Vetuschi A. Morini S. Attili A.F. Gaudio E. Effect of ovariectomy on the proliferative capacity of intrahepatic rat cholangiocytes.Gastroenterology. 2002; 123: 336-344Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 29Alvaro D. Onori P. Metalli V.D. Svegliati-Baroni G. Folli F. Franchitto A. Alpini G. Mancino M.G. Attili A.F. Gaudio E. Intracellular pathways mediating estrogen-induced cholangiocyte proliferation in the rat.Hepatology. 2002; 36: 297-304Crossref PubMed Scopus (82) Google Scholar, 30Svegliati-Baroni G. Ghiselli R. Marzioni M. Alvaro D. Mocchegiani F. Saccomanno S. Sisti V. Ugili L. Orlando F. Alpini G. Saba V. Benedetti A. Estrogens maintain bile duct mass and reduce apoptosis after biliodigestive anastomosis in bile duct ligated rats.J Hepatol. 2006; 44: 1158-1166Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 31Alvaro D. Invernizzi P. Onori P. Franchitto A. De Santis A. Crosignani A. Sferra R. Ginanni-Corradini S. Mancino M.G. Maggioni M. Attili A.F. Podda M. Gaudio E. Estrogen receptors in cholangiocytes and the progression of primary biliary cirrhosis.J Hepatol. 2004; 41: 905-912Abstract Full Text Full Text PDF PubMed Scopus (99) Google ScholarGastrinCCK-B/gastrinCounteracts the effect of secretin; inhibits cholangiocyte proliferation during BDL32Glaser S. Benedetti A. Marucci L. Alvaro D. Baiocchi L. Kanno N. Caligiuri A. Phinizy J.L. Chowdhury U. Papa E. LeSage G. Alpini G. Gastrin inhibits cholangiocyte growth in bile duct-ligated rats by interaction with cholecystokinin-B/Gastrin receptors via D-myo-inositol 1,4,5-triphosphate-.Ca(2+)-, and protein kinase C α-dependent mechanisms, Hepatology. 2000; 32: 17-25Google Scholar, 33Glaser S. Rodgers R.E. Phinizy J.L. Robertson W.E. Lasater J. Caligiuri A. Tretjak Z. LeSage G. Alpini G. Gastrin inhibits secretin-induced ductal secretion by interaction with specific receptors on rat cholangiocytes.Am J Physiol Gastrointest Liver Physiol. 1997; 273: G1061-G1070Google ScholarGH/IGF-1GH-R/IGF1RStimulates cholangiocyte proliferation; GH stimulates production and release of IGF-1 that modulates cell proliferation34Alvaro D. Metalli V.D. Alpini G. Onori P. Franchitto A. Barbaro B. Glaser S. Francis H. Cantafora A. Blotta I. Attili A.F. Gaudio E. The intrahepatic biliary epithelium is a target of the growth hormone/insulin-like growth factor 1 axis.J Hepatol. 2005; 43: 875-883Abstract Full Text Full Text PDF PubMed Scopus (59) Google ScholarGLP-1 (exendin-4)GLP-1RGLP-1 is expressed by cholestatic cholangiocytes; stimulates biliary proliferation; exendin-4 protects cholangiocytes from apoptosis35Marzioni M. Alpini G. Saccomanno S. Candelaresi C. Venter J. Rychlicki C. Fava G. Francis H. Trozzi L. Glaser S. Benedetti A. Glucagon-like peptide-1 and its receptor agonist exendin-4 modulate cholangiocyte adaptive response to cholestasis.Gastroenterology. 2007; 133: 244-255Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 36Marzioni M. Alpini G. Saccomanno S. Candelaresi C. Venter J. Rychlicki C. Fava G. Francis H. Trozzi L. Benedetti A. Exendin-4, a glucagon-like peptide 1 receptor agonist, protects cholangiocytes from apoptosis.Gut. 2009; 58: 990-997Crossref PubMed Scopus (50) Google ScholarNGFTrkASecreted by cholestatic cholangiocytes; supports the proliferative response to BDL37Gigliozzi A. Alpini G. Baroni G.S. Marucci L. Metalli V.D. Glaser S. Francis H. Mancino M.G. Ueno Y. Barbaro B. Benedetti A. Attili A.F. Alvaro D. Nerve growth factor modulates the proliferative capacity of the intrahepatic biliary epithelium in experimental cholestasis.Gastroenterology. 2004; 127: 1198-1209Abstract Full Text Full Text PDF PubMed Scopus (71) Google ScholarProgesteronePR-A/B; mPRStimulates proliferation in normal and cholestatic cholangiocytes via autocrine/paracrine mechanisms38Glaser S. DeMorrow S. Francis H. Ueno Y. Gaudio E. Vaculin S. Venter J. Franchitto A. Onori P. Vaculin B. Marzioni M. Wise C. Pilanthananond M. Savage J. Pierce L. Mancinelli R. Alpini G. Progesterone stimulates the proliferation of female and male cholangiocytes via autocrine/paracrine mechanisms.Am J Physiol Gastrointest Liver Physiol. 2008; 295: G124-G136Crossref PubMed Scopus (34) Google ScholarSecretinSRStimulates proliferation of normal and cholestatic cholangiocytes; lack of SR reduces biliary hyperplasia in response to BDL39Glaser S. Lam I.P. Franchitto A. Gaudio E. Onori P. Chow B.K. Wise C. Kopriva S. Venter J. White M. Ueno Y. Dostal D. Carpino G. Mancinelli R. Butler W. Chiasson V. DeMorrow S. Francis H. Alpini G. Knockout of secretin receptor reduces large cholangiocyte hyperplasia in mice with extrahepatic cholestasis induced by bile duct ligation.Hepatology. 2010; 52: 204-214Crossref PubMed Scopus (71) Google ScholarSomatostatinSSTR2Counteracts the effect of secretin-stimulated biliary secretion; inhibits proliferation40Alpini G. Glaser S. Ueno Y. Pham L. Podila P.V. Caligiuri A. LeSage G. LaRusso N.F. Heterogeneity of the proliferative capacity of rat cholangiocytes after bile duct ligation.Am J Physiol Gastrointest Liver Physiol. 1998; 274: G767-G775PubMed Google Scholar, 41Tietz P.S. Alpini G. Pham L.D. LaRusso N.F. Somatostatin inhibits secretin-induced ductal hypercholeresis and exocytosis by cholangiocytes.Am J Physiol. 1995; 269: G110-G118PubMed Google Scholar, 42Tracy Jr, T.F. Tector A.J. Goerke M.E. Kitchen S. Lagunoff D. Somatostatin analogue (octreotide) inhibits bile duct epithelial cell proliferation and fibrosis after extrahepatic biliary obstruction.Am J Pathol. 1993; 143: 1574-1578PubMed Google ScholarVEGFVEGR2 and 3Secreted by cholangiocytes during cholestasis and stimulates an increase in biliary proliferation; prevents cholangiocyte apoptosis induced by interruption of the blood flow of the hepatic artery; VEGF receptor inhibitor, SU-5416, blocked liver cyst growth in Pkd2WS25/– mice43Gaudio E. Barbaro B. Alvaro D. Glaser S. Francis H. Ueno Y. Meininger C.J. Franchitto A. Onori P. Marzioni M. Taffetani S. Fava G. Stoica G. Venter J. Reichenbach R. De Morrow S. Summers R. Alpini G. Vascular endothelial growth factor stimulates rat cholangiocyte proliferation via an autocrine mechanism.Gastroenterology. 2006; 130: 1270-1282Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 44Gaudio E. Barbaro B. Alvaro D. Glaser S. Francis H. Franchitto A. Onori P. Ueno Y. Marzioni M. Fava G. Venter J. Reichenbach R. Summers R. Alpini G. Administration of r-VEGF-A prevents hepatic artery ligation-induced bile duct damage in bile duct ligated rats.Am J Physiol Gastrointest Liver Physiol. 2006; 291: G307-G317Crossref PubMed Scopus (59) Google Scholar, 45Fabris L. Cadamuro M. Fiorotto R. Roskams T. Spirli C. Melero S. Sonzogni A. Joplin R.E. Okolicsanyi L. Strazzabosco M. Effects of angiogenic factor overexpression by human and rodent cholangiocytes in polycystic liver diseases.Hepatology. 2006; 43: 1001-1012Crossref PubMed Scopus (117) Google Scholar, 46Amura C.R. Brodsky K.S. Groff R. Gattone V.H. Voelkel N.F. Doctor R.B. VEGF receptor inhibition blocks liver cyst growth in pkd2(WS25/-) mice.Am J Physiol Cell Physiol. 2007; 293: C419-C428Crossref PubMed Scopus (54) Google ScholarET-1ETA and ETBET-1 inhibits secretin-induced ductal secretion47Caligiuri A. Glaser S. Rodgers R.E. Phinizy J.L. Robertson W. Papa E. Pinzani M. Alpini G. Endothelin-1 inhibits secretin-stimulated ductal secretion by interacting with ETA receptors on large cholangiocytes.Am J Physiol Gastrointest Liver Physiol. 1998; 275: G835-G846Google ScholarCytokines (IL-6, IL-8)gp130 CXCR2CXCR2 agonists in ADPKD liver cyst fluids promote cholangiocyte proliferation; IL-6 and IL-8 are secreted by cholangiocytes48Amura C.R. Brodsky K.S. Gitomer B. McFann K. Lazennec G. Nichols M.T. Jani A. Schrier R.W. Doctor R.B. CXCR2 agonists in ADPKD liver cyst fluids promote cell proliferation.Am J Physiol Cell Physiol. 2008; 294: C786-C796Crossref PubMed Scopus (21) Google ScholarProlactinProlactin receptor (short and long)Stimulates the proliferation of normal female cholangiocytes by differential regulation of Ca2+-dependent PKC isoforms49Taffetani S. Glaser S. Francis H. DeMorrow S. Ueno Y. Alvaro D. Marucci L. Marzioni M. Fava G. Venter J. Vaculin S. Vaculin B. Lam I.P. Lee V.H. Gaudio E. Carpino G. Benedetti A. Alpini G. Prolactin stimulates the proliferation of normal female cholangiocytes by differential regulation of Ca2+-dependent PKC isoforms.BMC Physiol. 2007; 7: 6Crossref PubMed Scopus (30) Google Scholar, 50Bogorad R.L. Ostroukhova T.Y. Orlova A.N. Rubtsov P.M. Smirnova O.V. Long isoform of prolactin receptor predominates in rat intrahepatic bile ducts and further increases under obstructive cholestasis.J Endocrinol. 2006; 188: 345-354Crossref PubMed Scopus (19) Google ScholarFSHFSH receptorInduces biliary hyperplasia via an autocrine mechanism by the activation of cAMP-dependent ERK1/2 and Elk-151Mancinelli R. Onori P. Gaudio E. DeMorrow S. Franchitto A. Francis H. Glaser S. Carpino G. Venter J. Alvaro D. Kopriva S. White M. Kossie A. Savage J. Alpini G. Follicle-stimulating hormone increases cholangiocyte proliferation by an autocrine mechanism via cAMP-dependent phosphorylation of ERK1/2 and Elk-1.Am J Physiol Gastrointest Liver Physiol. 2009; 297: G11-G26Crossref PubMed Scopus (49) Google ScholarCLR, calcitonin receptor-like receptor; Elk-1, ets-like gene-1; GH, growth hormone; IL-6, interleukin-6; RAMP1, receptor activity-modifying protein 1; RCP, receptor component protein; TrkA, neurotrophic tyrosine kinase receptor type 1. Open table in a new tab AP-1, activator protein-1; AR, androgen receptor; OR, opiod receptor; RAMH, R-α-methylhistamine dihydrobromide. CLR, calcitonin receptor-like receptor; Elk-1, ets-like gene-1; GH, growth hormone; IL-6, interleukin-6; RAMP1, receptor activity-modifying protein 1; RCP, receptor component protein; TrkA, neurotrophic tyrosine kinase receptor type 1. The intrahepatic biliary epithelium is divided into extrahepatic and intrahepatic bile ducts.52Kanno N. LeSage G. Glaser S. Alvaro D. Alpini G. Functional heterogeneity of the intrahepatic biliary epithelium.Hepatology. 2000; 31: 555-561Crossref PubMed Scopus (109) Google Scholar, 53Ludwig J. New concepts in biliary