The Secretin/Secretin Receptor Axis Modulates Ductular Reaction and Liver Fibrosis through Changes in Transforming Growth Factor-β1-Mediated Biliary Senescence.

Abstract

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-β1 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-β1 biliary secretion. Targeting senescent cholangiocytes may represent a novel therapeutic approach for ameliorating hepatic fibrosis during cholestatic liver injury.

• Authors: Nan Wu, Fanyin Meng, Tianhao Zhou, Julie Venter, Thao K Giang, Konstantina Kyritsi, Chaodong Wu, Domenico Alvaro, Paolo Onori, Romina Mancinelli, Eugenio Gaudio, Heather Francis, Gianfranco Alpini, Shannon Glaser, Antonio Franchitto
• Journal: The American journal of pathology (Am J Pathol) Vol. 188 Issue 10 Pg. 2264-2280 (10 2018) ISSN: 1525-2191 [Electronic] United States
• PMID: 30036520 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• RNA, Messenger
• Receptors, G-Protein-Coupled
• Receptors, Gastrointestinal Hormone
• Tgfb1 protein, mouse
• Transforming Growth Factor beta1
• secretin receptor
• Secretin

Topics

• Animals
• Bile Ducts (cytology)
• Cellular Senescence (physiology)
• Kupffer Cells (metabolism)
• Liver Cirrhosis (physiopathology)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Organ Size
• RNA, Messenger (metabolism)
• Receptors, G-Protein-Coupled (physiology)
• Receptors, Gastrointestinal Hormone (physiology)
• Secretin (metabolism, pharmacology)
• Transforming Growth Factor beta1 (physiology)