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.

Secretin/secretin receptor signaling mediates biliary damage and liver fibrosis in early-stage primary biliary cholangitis / Kennedy, Lindsey; Francis, Heather; Invernizzi, Pietro; Venter, Julie; Wu, Nan; Carbone, Marco; Gershwin, M Eric; Bernuzzi, Francesca; Franchitto, Antonio; Alvaro, Domenico; Marzioni, Marco; Onori, Paolo; Gaudio, Eugenio; Sybenga, Amelia; Fabris, Luca; Meng, Fanyin; Glaser, Shannon; Alpini, Gianfranco. - In: THE FASEB JOURNAL. - ISSN 0892-6638. - 33:9(2019), pp. 10269-10279. [10.1096/fj.201802606R]

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

Carbone, Marco;Franchitto, Antonio;Alvaro, Domenico;Onori, Paolo;Gaudio, Eugenio;
2019

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.
2019
angiogenesis; cellular senescence; cholangiopathies; liver damage; miR-125b
01 Pubblicazione su rivista::01a Articolo in rivista
Secretin/secretin receptor signaling mediates biliary damage and liver fibrosis in early-stage primary biliary cholangitis / Kennedy, Lindsey; Francis, Heather; Invernizzi, Pietro; Venter, Julie; Wu, Nan; Carbone, Marco; Gershwin, M Eric; Bernuzzi, Francesca; Franchitto, Antonio; Alvaro, Domenico; Marzioni, Marco; Onori, Paolo; Gaudio, Eugenio; Sybenga, Amelia; Fabris, Luca; Meng, Fanyin; Glaser, Shannon; Alpini, Gianfranco. - In: THE FASEB JOURNAL. - ISSN 0892-6638. - 33:9(2019), pp. 10269-10279. [10.1096/fj.201802606R]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1295512
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