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The physiological roles of secretin and its receptor.

ABSTRACT: Secretin is secreted by S cells in the small intestine and affects the function of a number of organ systems. Secretin receptors (SR) are expressed in the basolateral domain of several cell types. In addition to regulating the secretion of a number of epithelia (e.g., in the pancreas and biliary epithelium in the liver), secretin exerts trophic effects in several cell types. In this article, we will provide a comprehensive review on the multiple roles of secretin and SR signaling in the regulation of epithelial functions in various organ systems with particular emphasis in the liver. We will discuss the role of secretin and its receptor in health and biliary disease pathogenesis. Finally, we propose future areas of research for the further evaluation of the secretin/secretin receptor axis in liver pathophysiology.

SUBMITTER: Afroze S

PROVIDER: S-EPMC4200670 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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The physiological roles of secretin and its receptor.

Afroze Syeda S Meng Fanyin F Jensen Kendal K McDaniel Kelly K Rahal Kinan K Onori Paolo P Gaudio Eugenio E Alpini Gianfranco G Glaser Shannon S SS

Annals of translational medicine 20131001 3

Secretin is secreted by S cells in the small intestine and affects the function of a number of organ systems. Secretin receptors (SR) are expressed in the basolateral domain of several cell types. In addition to regulating the secretion of a number of epithelia (e.g., in the pancreas and biliary epithelium in the liver), secretin exerts trophic effects in several cell types. In this article, we will provide a comprehensive review on the multiple roles of secretin and SR signaling in the regulati ...[more]

PMID: 25332973

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| S-EPMC2464459 | biostudies-literature

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The secretin/secretin receptor axis modulates liver fibrosis through changes in transforming growth factor-?1 biliary secretion in mice.

Project description:The secretin/secretin receptor (SR) axis is up-regulated by proliferating cholangiocytes during cholestasis. Secretin stimulates biliary proliferation by down-regulation of let-7a and subsequent up-regulation of the growth-promoting factor, nerve growth factor (NGF). It is not known whether the secretin/SR axis plays a role in subepithelial fibrosis observed during cholestasis. Our aim was to determine the role of the secretin/SR axis in activation of biliary fibrosis in animal models and human primary sclerosing cholangitis (PSC). Studies were performed in wild-type (WT) mice with bile duct ligation (BDL), BDL SR(-/-) mice, or Mdr2(-/-) mouse models of cholestatic liver injury. In selected studies, the SR antagonist (Sec 5-27) was used to block the secretin/SR axis. Biliary proliferation and fibrosis were evaluated as well as secretion of secretin (by cholangiocytes and S cells), expression of markers of fibrosis, transforming growth factor-?1 (TGF-?1), transforming growth factor-?1 receptor (TGF-?1R), let-7a, and downstream expression of NGF. Correlative studies were performed in human control and PSC liver tissue biopsies, serum, and bile. SR antagonist reduced biliary proliferation and hepatic fibrosis in BDL WT and Mdr2(-/-) mice. There was decreased expression of let-7a in BDL and Mdr2(-/-) cholangiocytes that was associated with increased NGF expression. Inhibition of let-7a accelerated liver fibrosis was attributed to cholestasis. There was increased expression of TGF-?1 and TGF-?1R. Significantly higher expression of secretin, SR, and TGF-?1 was observed in PSC patient liver samples compared to healthy controls. In addition, there was higher expression of fibrosis genes and remarkably decreased expression of let-7a and increased expression of NGF compared to the control.The secretin/SR axis plays a key role in regulating the biliary contribution to cholestasis-induced hepatic fibrosis. (Hepatology 2016;64:865-879).

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The Secretin/Secretin Receptor Axis Modulates Ductular Reaction and Liver Fibrosis through Changes in Transforming Growth Factor-?1-Mediated Biliary Senescence.

Project description:Activation of the secretin (Sct)/secretin receptor (SR) axis stimulates ductular reaction and liver fibrosis, which are hallmarks of cholangiopathies. Our aim was to define the role of Sct-regulated cellular senescence, and we demonstrated that both ductular reaction and liver fibrosis are significantly reduced in Sct-/-, SR-/-, and Sct-/-/SR-/- bile duct ligated (BDL) mice compared with BDL wild-type mice. The reduction in hepatic fibrosis in Sct-/-, SR-/-, and Sct-/-/SR-/- BDL mice was accompanied by reduced transforming growth factor-?1 levels in serum and cholangiocyte supernatant, as well as decreased expression of markers of cellular senescence in cholangiocytes in contrast to enhanced cellular senescence in hepatic stellate cells compared with BDL wild-type mice. Secretin directly stimulated the senescence of cholangiocytes and regulated, by a paracrine mechanism, the senescence of hepatic stellate cells and liver fibrosis via modulation of transforming growth factor-?1 biliary secretion. Targeting senescent cholangiocytes may represent a novel therapeutic approach for ameliorating hepatic fibrosis during cholestatic liver injury.

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