Primary biliary cholangitis (PBC) primarily targets cholangiocytes and is characterized by liver fibrosis and biliary proliferation. Activation of the secretin (Sct)/secretin receptor (SR) axis, expressed only by cholangiocytes, increases biliary proliferation, liver fibrosis, and bicarbonate secretion. We evaluated the effectiveness of SR antagonist treatment for early-stage PBC. Male and female dominant-negative TGF-β receptor II (dnTGF-βRII) (model of PBC) and wild-type mice at 12 wk of age were treated with saline or the SR antagonist, Sec 5-27, for 1 wk. dnTGF-βRII mice expressed features of early-stage PBC along with enhanced Sct/SR axis activation and Sct secretion. dnTGF-βRII mice had increased biliary proliferation or senescence, inflammation, and liver fibrosis. In dnTGF-βRII mice, there was increased microRNA-125b/TGF-β1/TGF-β receptor 1/VEGF-A signaling. Human early-stage PBC patients had an increase in hepatobiliary Sct and SR expression and serum Sct levels. Increased biliary Sct/SR signaling promotes biliary and hepatic damage during early-stage PBC.-Kennedy, L., Francis, H., Invernizzi, P., Venter, J., Wu, N., Carbone, M., Gershwin, M. E., Bernuzzi, F., Franchitto, A., Alvaro, D., Marzioni, M., Onori, P., Gaudio, E., Sybenga, A., Fabris, L., Meng, F., Glaser, S., Alpini, G. Secretin/secretin receptor signaling mediates biliary damage and liver fibrosis in early-stage primary biliary cholangitis.
Keywords: angiogenesis; cellular senescence; cholangiopathies; liver damage; miR-125b.
Conflict of interest statement
Portions of this work were supported by Veterans Affairs Merit Awards (1I01BX003031 to H.F., 4I01BX000574 to G.A., and 1I01BX001724 to F.M.) from the United States Department of Veteran’s Affairs, Biomedical Laboratory Research and Development Service; U.S. National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases Grants DK054811, DK076898, DK107310, DK110035, DK062975 (to G.A., S.G., and F.M.), DK108959 (to H.F.), and NIH National Institute on Alcohol Abuse and Alcoholism Grants AA025997 and AA025157 to F.M., S.G., and G.A.; The Partners Seeking a Cure (PSC) Grant Award 460933-00001 and Dr. Nicholas C. Hightower Centennial Chair of Gastroenterology from Baylor Scott & White Health (to G.A.); and Development Service by University of Rome “La Sapienza” (to P.O.). This material is the result of work supported with resources and the use of facilities at the Central Texas Veterans Health Care System (Temple, Texas, USA). The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Veteran’s Affairs or the United States Government. F.M., S.G., and G.A. share senior authorship. The authors declare no conflicts of interest.
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