Altered Notch ligand expression in human liver disease: further evidence for a role of the Notch signaling pathway in hepatic neovascularization and biliary ductular defects

Am J Pathol. 2002 May;160(5):1695-703. doi: 10.1016/S0002-9440(10)61116-9.


The Jagged and Delta family of transmembrane proteins are ligands for Notch receptors, which control the proliferation and/or differentiation of many cell lineages. Expression and localization of these ligands in the adult human liver has not been fully elucidated, nor whether dysregulation of these proteins contributes to liver disease processes. We have examined expression of the five known Notch ligands in human liver. Expression of Jagged-1 and Delta-4 mRNA was seen in normal and diseased liver tissue, whereas Jagged-2, Delta-1, and Delta-3 mRNA was undetectable. In primary liver cell isolates, Jagged-1 expression was found in all cell types, whereas Delta-4 was present in biliary epithelial and liver endothelial cells, but absent in hepatocytes. Interestingly, Jagged-1 mRNA expression was significantly up-regulated in diseased liver tissue. By immunohistochemistry, Jagged-1 expression was present on most structures in normal tissue. However in disease, strikingly strong Jagged-1 immunoreactivity was observed on many small neovessels and bile ductules. The expression of downstream modulators and effectors of Notch signaling was also detectable in purified cell isolates. This, together with aberrant Jagged-1 expression suggests that the Notch signaling pathway may play a role in the neovascularization and biliary defects observed in the liver during the development of cirrhosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Bile Ducts / chemistry
  • Bile Ducts / pathology
  • Calcium-Binding Proteins
  • Gene Expression
  • Humans
  • Immunohistochemistry
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Jagged-1 Protein
  • Liver / blood supply
  • Liver / chemistry
  • Liver / pathology
  • Liver Diseases / genetics
  • Liver Diseases / metabolism
  • Liver Diseases / pathology*
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology
  • Microscopy, Fluorescence
  • Neovascularization, Pathologic
  • Proteins / genetics*
  • Proteins / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Notch
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serrate-Jagged Proteins
  • Signal Transduction


  • Calcium-Binding Proteins
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • JAG1 protein, human
  • Jagged-1 Protein
  • Membrane Proteins
  • Proteins
  • RNA, Messenger
  • Receptors, Notch
  • Serrate-Jagged Proteins
  • delta protein