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

Abstract
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.
AuthorsKi-Hyun Kim, Chih-Chiun Chen, Gianfranco Alpini, Lester F Lau
JournalThe Journal of clinical investigation (J Clin Invest) Vol. 125 Issue 5 Pg. 1886-900 (May 2015) ISSN: 1558-8238 [Electronic] United States
PMID25822023 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • CYR61 protein, human
  • Calcium-Binding Proteins
  • Cyr61 protein, mouse
  • Cysteine-Rich Protein 61
  • Integrin alphaVbeta3
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NF-kappa B
  • Receptors, Notch
  • Receptors, Vitronectin
  • Recombinant Fusion Proteins
  • integrin alphaVbeta5
  • ligatin
  • Serrate proteins
Topics
  • Animals
  • Bile Ducts (metabolism, physiology)
  • Calcium-Binding Proteins (biosynthesis, genetics, pharmacology, therapeutic use)
  • Cell Division
  • Cells, Cultured
  • Cholestasis, Extrahepatic (genetics, metabolism, pathology)
  • Cysteine-Rich Protein 61 (genetics, pharmacology, physiology)
  • Gene Expression Regulation
  • Gene Knock-In Techniques
  • Hepatic Stellate Cells (metabolism)
  • Hepatocytes (metabolism)
  • Humans
  • Integrin alphaVbeta3
  • Intercellular Signaling Peptides and Proteins (biosynthesis, genetics, pharmacology, therapeutic use)
  • Liver (metabolism)
  • Membrane Proteins (biosynthesis, genetics, pharmacology, therapeutic use)
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B (metabolism)
  • RNA Interference
  • Receptors, Notch (physiology)
  • Receptors, Vitronectin (physiology)
  • Recombinant Fusion Proteins (metabolism)
  • Regeneration

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