Loss of Keratin 19 Favours the Development of Cholestatic Liver Disease Through Decreased Ductular Reaction

J Pathol. 2015 Nov;237(3):343-54. doi: 10.1002/path.4580. Epub 2015 Aug 3.

Abstract

Keratins (K) are cytoprotective proteins and keratin mutations predispose to the development of multiple human diseases. K19 represents the most widely used marker of biliary and hepatic progenitor cells as well as a marker of ductular reaction that constitutes the basic regenerative response to chronic liver injury. In the present study, we investigated the role of K19 in biliary and hepatic progenitor cells and its importance for ductular reaction. K19 wild-type (WT) and knockout (KO) mice were fed: (a) 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC); (b) cholic acid (CA); (c) a choline-deficient, ethionine-supplemented (CDE) diet; or (d) were subjected to common bile duct ligation (CBDL). The bile composition, liver damage, bile duct proliferation, oval cell content and biliary fibrosis were analysed. In untreated animals, loss of K19 led to redistribution of the K network in biliary epithelial cells (BECs) but to no obvious biliary phenotype. After DDC feeding, K19 KO mice exhibited (compared to WTs): (a) increased cholestasis; (b) less pronounced ductular reaction with reduced ductular proliferation and fewer oval cells; (c) impaired Notch 2 signalling in BECs; (d) lower biliary fibrosis score and biliary bicarbonate concentration. An attenuated oval cell proliferation in K19 KOs was also found after feeding with the CDE diet. K19 KOs subjected to CBDL displayed lower BEC proliferation, oval cell content and less prominent Notch 2 signal. K19 deficiency did not change the extent of CA- or CBDL-induced liver injury and fibrosis. Our results demonstrate that K19 plays an important role in the ductular reaction and might be of importance in multiple chronic liver disorders that frequently display a ductular reaction.

Keywords: DDC; cholangitis; ductular reaction; intermediate filament; stem cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Chemical and Drug Induced Liver Injury / etiology
  • Chemical and Drug Induced Liver Injury / genetics
  • Chemical and Drug Induced Liver Injury / metabolism*
  • Chemical and Drug Induced Liver Injury / pathology
  • Cholangitis, Sclerosing / chemically induced
  • Cholangitis, Sclerosing / genetics
  • Cholangitis, Sclerosing / metabolism*
  • Cholangitis, Sclerosing / pathology
  • Cholestasis, Extrahepatic / etiology
  • Cholestasis, Extrahepatic / genetics
  • Cholestasis, Extrahepatic / metabolism*
  • Cholestasis, Extrahepatic / pathology
  • Cholic Acid
  • Choline Deficiency / complications
  • Common Bile Duct / metabolism*
  • Common Bile Duct / pathology
  • Common Bile Duct / surgery
  • Disease Models, Animal
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Ethionine
  • Keratin-19 / deficiency*
  • Keratin-19 / genetics
  • Ligation
  • Liver / metabolism*
  • Liver / pathology
  • Liver Cirrhosis, Biliary / chemically induced
  • Liver Cirrhosis, Biliary / genetics
  • Liver Cirrhosis, Biliary / metabolism*
  • Liver Cirrhosis, Biliary / pathology
  • Liver Regeneration
  • Male
  • Mice, Knockout
  • Phenotype
  • Pyridines
  • Signal Transduction
  • Stem Cells / metabolism*
  • Stem Cells / pathology
  • Time Factors

Substances

  • 3,5-diethoxycarbonyl-1,4-dihydrocollidine
  • Keratin-19
  • Pyridines
  • Cholic Acid
  • Ethionine