CCN1 induces hepatic ductular reaction through integrin αvβ₅-mediated activation of NF-κB

J Clin Invest. 2015 May;125(5):1886-900. doi: 10.1172/JCI79327. Epub 2015 Mar 30.


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-κB through integrin αvβ5/αvβ3, 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-κB or NOTCH signaling. Knock-in mice expressing a CCN1 mutant that is unable to bind αvβ5/αvβ3 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 αvβ5/αvβ3, NF-κB, 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/αvβ5/NF-κB/JAG1 as a critical axis for biliary injury repair.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Bile Ducts / metabolism*
  • Bile Ducts / physiology
  • Calcium-Binding Proteins / biosynthesis
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / pharmacology
  • Calcium-Binding Proteins / therapeutic use
  • Cell Division
  • Cells, Cultured
  • Cholestasis, Extrahepatic / genetics
  • Cholestasis, Extrahepatic / metabolism
  • Cholestasis, Extrahepatic / pathology
  • Cysteine-Rich Protein 61 / genetics
  • Cysteine-Rich Protein 61 / pharmacology
  • Cysteine-Rich Protein 61 / physiology*
  • Gene Expression Regulation
  • Gene Knock-In Techniques
  • Hepatic Stellate Cells / metabolism
  • Hepatocytes / metabolism
  • Humans
  • Integrin alphaVbeta3
  • Intercellular Signaling Peptides and Proteins / biosynthesis
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / pharmacology
  • Intercellular Signaling Peptides and Proteins / therapeutic use
  • Jagged-1 Protein
  • Liver / metabolism*
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics
  • Membrane Proteins / pharmacology
  • Membrane Proteins / therapeutic use
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism*
  • RNA Interference
  • Receptors, Notch / physiology
  • Receptors, Vitronectin / physiology*
  • Recombinant Fusion Proteins / metabolism
  • Regeneration
  • Serrate-Jagged Proteins


  • CCN1 protein, human
  • CCN1 protein, mouse
  • Calcium-Binding Proteins
  • Cysteine-Rich Protein 61
  • Integrin alphaVbeta3
  • Intercellular Signaling Peptides and Proteins
  • JAG1 protein, human
  • Jag1 protein, mouse
  • Jagged-1 Protein
  • Membrane Proteins
  • NF-kappa B
  • Receptors, Notch
  • Receptors, Vitronectin
  • Recombinant Fusion Proteins
  • Serrate-Jagged Proteins
  • integrin alphaVbeta5
  • ligatin