Secretin/secretin receptor signaling mediates biliary damage and liver fibrosis in early-stage primary biliary cholangitis

Lindsey Kennedy, Heather Francis, Pietro Invernizzi, Julie Venter, Nan Wu, Marco Carbone, M. Eric Gershwin, Francesca Bernuzzi, Antonio Franchitto, Domenico Alvaro, Marco Marzioni, Paolo Onori, Eugenio Gaudio, Amelia Sybenga, Luca Fabris, Fanyin Meng, Shannon Glaser, Gianfranco Alpini

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)10269-10279
Number of pages11
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume33
Issue number9
DOIs
StatePublished - Sep 1 2019

Keywords

  • angiogenesis
  • cellular senescence
  • cholangiopathies
  • liver damage
  • miR-125b

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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  • Cite this

    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. (2019). Secretin/secretin receptor signaling mediates biliary damage and liver fibrosis in early-stage primary biliary cholangitis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 33(9), 10269-10279. https://doi.org/10.1096/fj.201802606R