| First Author | Kim KH | Year | 2015 |
| Journal | J Clin Invest | Volume | 125 |
| Issue | 5 | Pages | 1886-900 |
| PubMed ID | 25822023 | Mgi Jnum | J:222419 |
| Mgi Id | MGI:5644593 | Doi | 10.1172/JCI79327 |
| Citation | Kim KH, et al. (2015) CCN1 induces hepatic ductular reaction through integrin alphavbeta(5)-mediated activation of NF-kappaB. J Clin Invest 125(5):1886-900 |
| abstractText | Liver cholestatic diseases, which stem from diverse etiologies, result in liver toxicity and fibrosis and may progress to cirrhosis and liver failure. We show that CCN1 (also known as CYR61), a matricellular protein that dampens and resolves liver fibrosis, also mediates cholangiocyte proliferation and ductular reaction, which are repair responses to cholestatic injury. In cholangiocytes, CCN1 activated NF-kappaB through integrin alphavbeta5/alphavbeta3, leading to Jag1 expression, JAG1/NOTCH signaling, and cholangiocyte proliferation. CCN1 also induced Jag1 expression in hepatic stellate cells, whereupon they interacted with hepatic progenitor cells to promote their differentiation into cholangiocytes. Administration of CCN1 protein or soluble JAG1 induced cholangiocyte proliferation in mice, which was blocked by inhibitors of NF-kappaB or NOTCH signaling. Knock-in mice expressing a CCN1 mutant that is unable to bind alphavbeta5/alphavbeta3 were impaired in ductular reaction, leading to massive hepatic necrosis and mortality after bile duct ligation (BDL), whereas treatment of these mice with soluble JAG1 rescued ductular reaction and reduced hepatic necrosis and mortality. Blockade of integrin alphavbeta5/alphavbeta3, NF-kappaB, or NOTCH signaling in WT mice also resulted in defective ductular reaction after BDL. These findings demonstrate that CCN1 induces cholangiocyte proliferation and ductular reaction and identify CCN1/alphavbeta5/NF-kappaB/JAG1 as a critical axis for biliary injury repair. |
