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 language | English (US) |
|---|---|
| Pages (from-to) | 10269-10279 |
| Number of pages | 11 |
| Journal | FASEB journal : official publication of the Federation of American Societies for Experimental Biology |
| Volume | 33 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 1 2019 |
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Keywords
- angiogenesis
- cellular senescence
- cholangiopathies
- liver damage
- miR-125b
ASJC Scopus subject areas
- Biotechnology
- Biochemistry
- Molecular Biology
- Genetics
Cite this
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: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Vol. 33, No. 9, 01.09.2019, p. 10269-10279.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Secretin/secretin receptor signaling mediates biliary damage and liver fibrosis in early-stage primary biliary cholangitis
AU - Kennedy, Lindsey
AU - Francis, Heather
AU - Invernizzi, Pietro
AU - Venter, Julie
AU - Wu, Nan
AU - Carbone, Marco
AU - Gershwin, M. Eric
AU - Bernuzzi, Francesca
AU - Franchitto, Antonio
AU - Alvaro, Domenico
AU - Marzioni, Marco
AU - Onori, Paolo
AU - Gaudio, Eugenio
AU - Sybenga, Amelia
AU - Fabris, Luca
AU - Meng, Fanyin
AU - Glaser, Shannon
AU - Alpini, Gianfranco
PY - 2019/9/1
Y1 - 2019/9/1
N2 - 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.
AB - 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.
KW - angiogenesis
KW - cellular senescence
KW - cholangiopathies
KW - liver damage
KW - miR-125b
UR - http://www.scopus.com/inward/record.url?scp=85071788352&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071788352&partnerID=8YFLogxK
U2 - 10.1096/fj.201802606R
DO - 10.1096/fj.201802606R
M3 - Article
C2 - 31251081
AN - SCOPUS:85071788352
VL - 33
SP - 10269
EP - 10279
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 9
ER -