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Article: Knockout of secretin receptor reduces large cholangiocyte hyperplasia in mice with extrahepatic cholestasis induced by bile duct ligation

TitleKnockout of secretin receptor reduces large cholangiocyte hyperplasia in mice with extrahepatic cholestasis induced by bile duct ligation
Authors
Issue Date2010
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/
Citation
Hepatology, 2010, v. 52 n. 1, p. 204-214 How to Cite?
AbstractDuring bile duct ligation (BDL), the growth of large cholangiocytes is regulated by the cyclic adenosine monophosphate (cAMP)/extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and is closely associated with increased secretin receptor (SR) expression. Although it has been suggested that SR modulates cholangiocyte growth, direct evidence for secretin-dependent proliferation is lacking. SR wild-type (WT) (SR+/+) or SR knockout (SR-/-) mice underwent sham surgery or BDL for 3 or 7 days. We evaluated SR expression, cholangiocyte proliferation, and apoptosis in liver sections and proliferating cell nuclear antigen (PCNA) protein expression and ERK1/2 phosphorylation in purified large cholangiocytes from WT and -/- BDL mice. Normal WT mice were treated with secretin (2.5 nmoles/kg/day by way of osmotic minipumps for 1 week), and biliary mass was evaluated. Small and large cholangiocytes were used to evaluate the in vitro effect of secretin (100 nM) on proliferation, protein kinase A (PKA) activity, and ERK1/2 phosphorylation. SR expression was also stably knocked down by short hairpin RNA, and basal and secretin-stimulated cAMP levels (a functional index of biliary growth) and proliferation were determined. SR was expressed by large cholangiocytes. Knockout of SR significantly decreased large cholangiocyte growth induced by BDL, which was associated with enhanced apoptosis. PCNA expression and ERK1/2 phosphorylation were decreased in large cholangiocytes from-/- BDL compared with WT BDL mice. In vivo administration of secretin to normal WT mice increased ductal mass. In vitro, secretin increased proliferation, PKA activity, and ERK1/2 phosphorylation of large cholangiocytes that was blocked by PKA and mitogen-activated protein kinase kinase inhibitors. Stable knockdown of SR expression reduced basal cholangiocyte proliferation. SR is an important trophic regulator sustaining biliary growth. Conclusion: The current study provides strong support for the potential use of secretin as a therapy for ductopenic liver diseases. Copyright © 2010 by the American Association for the Study of Liver Diseases.
Persistent Identifierhttp://hdl.handle.net/10722/127414
ISSN
2015 Impact Factor: 11.711
2015 SCImago Journal Rankings: 4.752
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Dr Nicholas C. Hightower Centennial Chair of Gastroenterology flow Scott White
VA
National Institutes of HealthDK58411
DK081442
DK078532
University Funds
PRIN2007HPT7BA_001
University of Rome
Funding Information:

Supported in part by the Dr Nicholas C. Hightower Centennial Chair of Gastroenterology flow Scott & White; the VA Research Scholar Award; a VA Merit Award; National Institutes of Health Grants DK58411 (to G. A.), DK081442 (to S. S. G.), and DK078532 (to S. D.); University Funds PRIN 2007 (to P O.); PRIN 2007 (n. 2007HPT7BA_001) and Federate Athenaeum finds from University of Rome "La Sapienza" (to E. G.).

References

 

DC FieldValueLanguage
dc.contributor.authorGlaser, Sen_HK
dc.contributor.authorLam, IPen_HK
dc.contributor.authorFranchitto, Aen_HK
dc.contributor.authorGaudio, Een_HK
dc.contributor.authorOnori, Pen_HK
dc.contributor.authorChow, BKen_HK
dc.contributor.authorWise, Cen_HK
dc.contributor.authorKopriva, Sen_HK
dc.contributor.authorVenter, Jen_HK
dc.contributor.authorWhite, Men_HK
dc.contributor.authorUeno, Yen_HK
dc.contributor.authorDostal, Den_HK
dc.contributor.authorCarpino, Gen_HK
dc.contributor.authorMancinelli, Ren_HK
dc.contributor.authorButler, Wen_HK
dc.contributor.authorChiasson, Ven_HK
dc.contributor.authorDeMorrow, Sen_HK
dc.contributor.authorFrancis, Hen_HK
dc.contributor.authorAlpini, Gen_HK
dc.date.accessioned2010-10-31T13:24:15Z-
dc.date.available2010-10-31T13:24:15Z-
dc.date.issued2010en_HK
dc.identifier.citationHepatology, 2010, v. 52 n. 1, p. 204-214en_HK
dc.identifier.issn0270-9139en_HK
dc.identifier.urihttp://hdl.handle.net/10722/127414-
dc.description.abstractDuring bile duct ligation (BDL), the growth of large cholangiocytes is regulated by the cyclic adenosine monophosphate (cAMP)/extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and is closely associated with increased secretin receptor (SR) expression. Although it has been suggested that SR modulates cholangiocyte growth, direct evidence for secretin-dependent proliferation is lacking. SR wild-type (WT) (SR+/+) or SR knockout (SR-/-) mice underwent sham surgery or BDL for 3 or 7 days. We evaluated SR expression, cholangiocyte proliferation, and apoptosis in liver sections and proliferating cell nuclear antigen (PCNA) protein expression and ERK1/2 phosphorylation in purified large cholangiocytes from WT and -/- BDL mice. Normal WT mice were treated with secretin (2.5 nmoles/kg/day by way of osmotic minipumps for 1 week), and biliary mass was evaluated. Small and large cholangiocytes were used to evaluate the in vitro effect of secretin (100 nM) on proliferation, protein kinase A (PKA) activity, and ERK1/2 phosphorylation. SR expression was also stably knocked down by short hairpin RNA, and basal and secretin-stimulated cAMP levels (a functional index of biliary growth) and proliferation were determined. SR was expressed by large cholangiocytes. Knockout of SR significantly decreased large cholangiocyte growth induced by BDL, which was associated with enhanced apoptosis. PCNA expression and ERK1/2 phosphorylation were decreased in large cholangiocytes from-/- BDL compared with WT BDL mice. In vivo administration of secretin to normal WT mice increased ductal mass. In vitro, secretin increased proliferation, PKA activity, and ERK1/2 phosphorylation of large cholangiocytes that was blocked by PKA and mitogen-activated protein kinase kinase inhibitors. Stable knockdown of SR expression reduced basal cholangiocyte proliferation. SR is an important trophic regulator sustaining biliary growth. Conclusion: The current study provides strong support for the potential use of secretin as a therapy for ductopenic liver diseases. Copyright © 2010 by the American Association for the Study of Liver Diseases.en_HK
dc.languageengen_HK
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/en_HK
dc.relation.ispartofHepatologyen_HK
dc.rightsHepatology. Copyright © John Wiley & Sons, Inc.en_HK
dc.subject.meshBile Ducts - drug effects - pathologyen_HK
dc.subject.meshCholestasis, Extrahepatic - complications - genetics - pathologyen_HK
dc.subject.meshLiver - drug effects - pathologyen_HK
dc.subject.meshLiver Diseases - etiology - pathologyen_HK
dc.subject.meshReceptors, Gastrointestinal Hormone - genetics - physiologyen_HK
dc.titleKnockout of secretin receptor reduces large cholangiocyte hyperplasia in mice with extrahepatic cholestasis induced by bile duct ligationen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0270-9139&volume=52&spage=204&epage=214&date=2010&atitle=Knock+out+of+secretin+receptors+reduces+large+cholangiocyte+hyperplasia+in+mice+with+extrahepatic+cholestasis+induced+by+bile+duct+ligation.en_HK
dc.identifier.emailChow, BK: bkcc@hku.hken_HK
dc.identifier.authorityChow, BK=rp00681en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1002/hep.23657en_HK
dc.identifier.pmid20578263-
dc.identifier.pmcidPMC3049759-
dc.identifier.scopuseid_2-s2.0-77954239364en_HK
dc.identifier.hkuros176301en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77954239364&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume52en_HK
dc.identifier.issue1en_HK
dc.identifier.spage204en_HK
dc.identifier.epage214en_HK
dc.identifier.isiWOS:000279409200022-
dc.publisher.placeUnited Statesen_HK
dc.identifier.f10003758971-
dc.identifier.scopusauthoridGlaser, S=7101907731en_HK
dc.identifier.scopusauthoridLam, IP=14050702700en_HK
dc.identifier.scopusauthoridFranchitto, A=6701756460en_HK
dc.identifier.scopusauthoridGaudio, E=7006542760en_HK
dc.identifier.scopusauthoridOnori, P=6701535351en_HK
dc.identifier.scopusauthoridChow, BK=7102826193en_HK
dc.identifier.scopusauthoridWise, C=24479105300en_HK
dc.identifier.scopusauthoridKopriva, S=25825299000en_HK
dc.identifier.scopusauthoridVenter, J=10145041300en_HK
dc.identifier.scopusauthoridWhite, M=16023283700en_HK
dc.identifier.scopusauthoridUeno, Y=7402070441en_HK
dc.identifier.scopusauthoridDostal, D=7003331982en_HK
dc.identifier.scopusauthoridCarpino, G=6508122425en_HK
dc.identifier.scopusauthoridMancinelli, R=35230417000en_HK
dc.identifier.scopusauthoridButler, W=36196143500en_HK
dc.identifier.scopusauthoridChiasson, V=6504066858en_HK
dc.identifier.scopusauthoridDeMorrow, S=14031157400en_HK
dc.identifier.scopusauthoridFrancis, H=7101842823en_HK
dc.identifier.scopusauthoridAlpini, G=7005824212en_HK

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