Knockout of Secretin Receptor Reduces Large Cholangiocyte Hyperplasia in Mice With Extrahepatic Cholestasis Induced by Bile Duct Ligation

Glaser, Shannon; Lam, Ian P. Y.; Franchitto, Antonio; Gaudio, Eugenio; Onori, Paolo; Chow, Billy K. C.; Wise, Candace; Kopriva, Shelley; Venter, Julie; White, Mellanie; Ueno, Yoshiyuki; Dostal, David E.; Carpino, Guido; Mancinelli, Romina; Butler, Wendy; Chiasson, Valorie L; DeMorrow, Sharon; Francis, Heather; Alpini, Gianfranco

doi:10.1002/hep.23657

Cited by 80 publications

(114 citation statements)

References 33 publications

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“…HDC Ϫ/Ϫ mice and the corresponding wild-type (WT) mice were subjected to BDL (25) for up to 7 days or sham surgery. Animals were housed at Scott & White Hospital Animal Facility and given free access to drinking water and chow.…”

Section: In Vivo Modelsmentioning

confidence: 99%

Knockout of histidine decarboxylase decreases bile duct ligation-induced biliary hyperplasia via downregulation of the histidine decarboxylase/VEGF axis through PKA-ERK1/2 signaling

Graf

Meng

Hargrove

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Histidine is converted to histamine by histidine decarboxylase (HDC). We have shown that cholangiocytes 1) express HDC, 2) secrete histamine, and 3) proliferate after histamine treatment via ERK1/2 signaling. In bile duct-ligated (BDL) rodents, there is enhanced biliary hyperplasia, HDC expression, and histamine secretion. This studied aimed to demonstrate that knockdown of HDC inhibits biliary proliferation via downregulation of PKA/ERK1/2 signaling. HDC(-/-) mice and matching wild-type (WT) were subjected to sham or BDL. After 1 wk, serum, liver blocks, and cholangiocytes were collected. Immunohistochemistry was performed for 1) hematoxylin and eosin, 2) intrahepatic bile duct mass (IBDM) by cytokeratin-19, and 3) HDC biliary expression. We measured serum and cholangiocyte histamine levels by enzyme immunoassay. In total liver or cholangiocytes, we studied: 1) HDC and VEGF/HIF-1α expression and 2) PCNA and PKA/ERK1/2 protein expression. In vitro, cholangiocytes were stably transfected with shRNA-HDC plasmids (or control). After transfection we evaluated pPKA, pERK1/2, and cholangiocyte proliferation by immunoblots and MTT assay. In BDL HDC(-/-) mice, there was decreased IBDM, PCNA, VEGF, and HDC expression compared with BDL WT mice. Histamine levels were decreased in BDL HDC(-/-). BDL HDC(-/-) livers were void of necrosis and inflammation compared with BDL WT. PKA/ERK1/2 protein expression (increased in WT BDL) was lower in BDL HDC(-/-) cholangiocytes. In vitro, knockdown of HDC decreased proliferation and protein expression of PKA/ERK1/2 compared with control. In conclusion, loss of HDC decreases BDL-induced biliary mass and VEGF/HIF-1α expression via PKA/ERK1/2 signaling. Our data suggest that HDC is a key regulator of biliary proliferation.

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Section: In Vivo Modelsmentioning

confidence: 99%

Knockout of histidine decarboxylase decreases bile duct ligation-induced biliary hyperplasia via downregulation of the histidine decarboxylase/VEGF axis through PKA-ERK1/2 signaling

Graf

Meng

Hargrove

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The cholangiocyte proliferative response in these animal models is associated with increased SCTR gene expression and elevated secretinstimulated cAMP levels. Furthermore, administration of secretin (2.5 nmol·kg body wt Ϫ1 ·day Ϫ1 ) intraperitoneally by osmotic minipumps for 1 wk stimulates the proliferation of large cholangiocytes, while the knockout of the SCTR inhibits their proliferation following bile duct ligation by ϳ50% (14).…”

mentioning

confidence: 99%

Insignificant effect of secretin in rodent models of polycystic kidney and liver disease

Wang

Ward

et al. 2012

American Journal of Physiology-Renal Physiology

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mice; and the impact of a nonfunctional secretin receptor on disease development in Pkd2 Ϫ/WS25 :SCTR Ϫ/Ϫ double mutants. Renal and hepatic secretin and secretin receptor mRNA and plasma secretin were increased in both models, and secretin receptor protein was increased in the kidneys and liver of Pkd2 Ϫ/WS25 mice. However, exogenous secretin administered subcutaneously via osmotic pumps had minimal or negligible effects and the absence of a functional secretin receptor had no influence on the severity of PKD or PLD.

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“…Bile ducts are known to proliferate in response to ligation of the main duct as part of what is believed to be a compensatory response. Recently, this proliferative response in large cholangiocytes was shown to be absent in Sctr Ϫ/Ϫ mice (16). Whether this response is triggered by increased pressure or cholestasis is unclear.…”

Section: Discussionmentioning

confidence: 99%

Secretin is not necessary for exocrine pancreatic development and growth in mice

Sans

Sabbatini

Ernst

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Adaptive exocrine pancreatic growth is mediated primarily by dietary protein and the gastrointestinal hormone cholecystokinin (CCK). Feeding trypsin inhibitors such as camostat (FOY-305) is known to induce CCK release and stimulate pancreatic growth. However, camostat has also been reported to stimulate secretin release and, because secretin often potentiates the action of CCK, it could participate in the growth response. Our aim was to test the role of secretin in pancreatic development and adaptive growth through the use of C57BL/6 mice with genetic deletion of secretin or secretin receptor. The lack of secretin in the intestine or the secretin receptor in the pancreas was confirmed by RT-PCR. Other related components, such as vasoactive intestinal polypeptide (VIP) receptors (VPAC(1) and VPAC(2)), were not affected. Secretin increased cAMP levels in acini from wild-type (WT) mice but had no effect on acini from secretin receptor-deleted mice, whereas VIP and forskolin still induced a normal response. Secretin in vivo failed to induce fluid secretion in receptor-deficient mice. The pancreas of secretin or secretin receptor-deficient mice was of normal size and histology, indicating that secretin is not necessary for normal pancreatic differentiation or maintenance. When WT mice were fed 0.1% camostat in powdered chow, the pancreas doubled in size in 1 wk, accompanied by parallel increases in protein and DNA. Camostat-fed littermate secretin and secretin receptor-deficient mice had similar pancreatic mass to WT mice. These results indicate that secretin is not required for normal pancreatic development or adaptive growth mediated by CCK.

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Knockout of Secretin Receptor Reduces Large Cholangiocyte Hyperplasia in Mice With Extrahepatic Cholestasis Induced by Bile Duct Ligation

Cited by 80 publications

References 33 publications

Knockout of histidine decarboxylase decreases bile duct ligation-induced biliary hyperplasia via downregulation of the histidine decarboxylase/VEGF axis through PKA-ERK1/2 signaling

Knockout of histidine decarboxylase decreases bile duct ligation-induced biliary hyperplasia via downregulation of the histidine decarboxylase/VEGF axis through PKA-ERK1/2 signaling

Insignificant effect of secretin in rodent models of polycystic kidney and liver disease

Secretin is not necessary for exocrine pancreatic development and growth in mice

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