Abstract
BACKGROUND & AIMS Tight junctions (TJs) establish tissue barriers that maintain osmotic homeostasis and, in the liver, isolate bile flow from the blood circulation. ZO-2/Tjp2 is a scaffold protein that tethers TJ transmembrane proteins to the actin cytoskeleton. Missense mutations in Tjp2 have recently been shown to cause progressive cholestatic liver disease in humans. However, the underlying mechanisms still remain elusive. To study the role of Tjp2 in cholestatic liver disease, we generated and characterized mice lacking Tjp2 in hepatocytes, cholangiocytes, or both.
METHODS Tjp2 was inactivated in the mouse liver (both in hepatocytes and cholangiocytes) or hepatocytes or cholangiocytes only. Liver function tests were carried out by biochemical analysis of plasma and liver samples and liver tissue was evaluated by immunohistochemistry and histology. The mice were also subjected to cholic acid (CA) diet to assess their susceptibility to liver insults.
RESULTS Deletion of Tjp2 in the mouse liver did not result in apparent changes in TJ structure and composition, but lead to progressive cholestasis with lower expression levels of the bile acid (BA) transporter ABCB11/Bsep and the detoxification enzyme Cyp2b10. Feeding a CA diet that is well tolerated by control mice caused severe cholestasis and necrotic liver injury in mice lacking hepatic Tjp2. Administration of a CAR agonist, TCPOBOP, protected these mice from CA induced injury by enhancing the expression of the detoxifying enzyme Cyp2b10 in hepatocytes. Mice lacking Tjp2 in only hepatocytes or in only cholangiocytes showed less severe CA diet induced liver injury.
CONCLUSION Loss of Tjp2 from hepatocytes and cholangiocytes both contribute to progressive cholestatic liver disease and higher susceptibility to liver injury. In hepatocytes, Tjp2 exerts a protective role by regulating expression levels of BA transporters and detoxification enzymes. The mice may provide a new animal model for cholestatic liver disease linked to Tjp2 mutations in humans.
Footnotes
The authors declare no conflict of interest
Abbreviations
- Alb
- albumin;
- ALT
- Serum alanine aminotransferase
- AST
- aspartate aminotransferase
- AP
- alkaline phosphatase
- BA
- bile acid
- CA
- cholic acid
- CAR
- constitutive androstane receptor
- cKO
- conditional knock-out,
- Cre
- Cre recombinase
- FXR
- farnesoid X receptor
- icKO
- inducible conditional knock-out
- icKOCC
- inducible cholangiocyte-specific knock-out
- icKOHC
- inducible hepatocyte-specific conditional knock-out
- Ocln
- occludin
- TCPOBOP
- 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene
- TJ
- tight junction
- ZO
- zonula occludens
- ZO-2
- zonula occludens-2
