AbstractsBiology & Animal Science

Loss of Keratin 19 predisposes to the development of cholestatic liver disease

by Yu Chen




Institution: Universität Ulm
Department: Medizinische Fakultät
Degree: PhD
Year: 2014
Record ID: 1117378
Full text PDF: http://vts.uni-ulm.de/docs/2014/9204/vts_9204_13801.pdf


Abstract

Keratins (K) are cytoprotective proteins and keratin mutations predispose to development of multiple human diseases. K19 represents the most widely used biliary and liver progenitor cell (LPC) marker. Since K19 variants were found in patients with primary biliary cirrhosis (PBC), we investigated the role of K19 in cholangiocytes and LPCs. K19 wild-type (WT) and knockout (KO) mice were fed 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet or were subjected to common bile duct ligation (CBDL). The bile composition, liver damage, ductular reaction, oval cell content and biliary fibrosis were analyzed. In untreated animals, loss of K19 led to re-distribution of K network in cholangiocytes, but no obvious biliary phenotype. After DDC feeding, K19-KO mice exhibited (compared to WTs) (i) increased cholestasis; (ii) less pronounced ductular reaction with lower atypical ductular proliferation and lower amount of oval cells; (iii) impaired Notch 2 signaling in cholangiocytes; (iv) lower biliary fibrosis and biliary bicarbonate concentration. K19 deficiency did not change the extent of CBDL-induced liver injury and fibrosis. In conclusions, our results demonstrate that K19 plays an important role in LPCs and in small, but not large cholangiocytes, the latter being targeted in CBDL. These findings may be relevant to human PBC that affects small cholangiocytes and displays strong activation of Notch signaling.