The secretin/secretin receptor axis modulates liver fibrosis through changes in transforming growth factor-β1 biliary secretion in mice.
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-β1 (TGF-β1), transforming growth factor-β1 receptor (TGF-β1R), 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-β1 and TGF-β1R. Significantly higher expression of secretin, SR, and TGF-β1 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).
Department of Medicine and Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, TX.
Nan
N
Wu
Research, Central Texas Veterans Health Care System, Temple, TX.|Scott & White Digestive Disease Research Center, Scott & White, Temple, TX.|Operational Funds, Baylor Scott & White, Temple, TX.|Department of Medicine and Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, TX.
Fanyin
F
Meng
Humanitas Clinical and Research Center, Rozzano, Milan, Italy.|Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy.
Pietro
P
Invernizzi
Humanitas Clinical and Research Center, Rozzano, Milan, Italy.|Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy.
Francesca
F
Bernuzzi
Department of Medicine and Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, TX.
Julie
J
Venter
Research, Central Texas Veterans Health Care System, Temple, TX.
Holly
H
Standeford
Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, La Sapienza, Rome, Italy.
Paolo
P
Onori
Department of Medicine, Universita' Politecnica delle Marche, Ancona, Italy.
Marco
M
Marzioni
Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Italy.
Domenico
D
Alvaro
Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, La Sapienza, Rome, Italy.|Eleonora Lorillard Spencer Cenci Foundation, Rome, Italy.
Antonio
A
Franchitto
Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, La Sapienza, Rome, Italy.
Eugenio
E
Gaudio
Research, Central Texas Veterans Health Care System, Temple, TX.|Scott & White Digestive Disease Research Center, Scott & White, Temple, TX.|Department of Medicine and Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, TX.
Shannon
S
Glaser
Research, Central Texas Veterans Health Care System, Temple, TX.|Scott & White Digestive Disease Research Center, Scott & White, Temple, TX.|Department of Medicine and Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, TX.
Gianfranco
G
Alpini
D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D015209:Cholangitis, Sclerosing / Q000150:complications* / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D012633:Secretin / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
D005353:Fibronectins; D035683:MicroRNAs; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone; D018125:Receptors, Transforming Growth Factor beta; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; C542687:mirnlet7 microRNA, mouse; C029937:secretin receptor; D012633:Secretin; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I