The zonula occludens protein family regulates the hepatic barrier system in the murine liver

The hepatic barrier is indispensable for the physiological functions of the liver and is impaired under various pathological conditions. Tight junctions reportedly play a central role in hepatic barrier regulation; however, there is limited direct evidence supporting this observation, with few in vivo models or confirmations of the implicated molecular mechanisms presented to date. We inactivated the tight junction component gene, Tjp2/ZO-2, and the related molecule, Tjp1/ZO-1, in mouse livers. In humans, TJP2/ZO-2 mutations have been implicated in the development of human progressive familial intrahepatic cholestasis 4 (PFIC4). The mice deficient in either ZO-1 or ZO-2 in the liver did not exhibit major abnormalities. However, the ablation of both molecules impaired the molecular architecture as well as the structure and function of hepatocyte tight junctions, which disrupted the hepatic barrier and was lethal to the mice by 6 weeks of age. In mutant mice, bile canaliculus formation and cellular polarity were compromised; also, transporter expression and localization were deregulated. Moreover, typical hepatic zonation and bile duct formation were inhibited, and sinusoidal vessels were disorganized. These findings clarify the role of tight junctions and polarity in the hepatic barrier as well as the effect that their disruption has on liver tissue. The observations also suggest that liver-specific ZO-1−/− and ZO-2−/− mice could be used as models for PFIC4, and this will provide new insights into liver pathophysiology and clinical applications. •The hepatic barrier is disrupted by the liver-specific ablation of ZO-1 and ZO-2.•ZO-1 or ZO-2 is required for tight junctions and apical polarity in hepatocytes.•Abcb11 and Abcc4 are dysfunctional in hepatocytes deficient of ZO-1 and ZO-2.•The loss of ZO-1 and ZO-2 impairs liver zonation, bile ducts, and sinusoids.•Mice deficient of liver-specific ZO-1 and ZO-2 could be a model for PFIC4.