TJP2/ZO-2-inactivating mutations in humans cause progressive cholestatic liver disease. Liver-specific deletion of Tjp2 in the mouse (Tjp2 cKO mice) leads to mild progressive cholestasis without an overt degradation of the bile-blood barrier (BBB). These mice are more susceptible to cholic acid (CA) induced liver injury. Interestingly, while initially also more susceptible, Tjp2 cKO mice develop tolerance to a DDC-supplemented diet. The DDC diet induces an exacerbated ductular reaction in Tjp2 cKO mice, which arises from the transdifferentiation of hepatocytes to cholangiocytes. Consequently, this transdifferentiation is only observed if Tjp2 is inactivated in hepatocytes, but not if deleted in cholangiocytes. The DDC-diet-induced hepatocyte transdifferentiation in Tjp2 cKO mice requires Yap and Wwtr1/Taz, whose protein expression is upregulated in hepatocytes lacking Tjp2, but is independent of Notch2. Although inactivating Tjp2 is sufficient for the upregulation of Yap and Wwtr1/Taz protein, efficient transdifferentiation requires the DDC-diet insult. Thus, Tjp2 negatively regulates Yap/Taz-mediated transdifferentiation of hepatocytes to cholangiocytes in response to DDC-diet-induced liver injury. Furthermore, transdifferentiation is regulated at multiple levels and the type of injury inflicted on the Tjp2 deficient liver plays an important role in the resulting pathophysiology.

人类的 TJP2/ZO-2失活突变导致进行性胆汁淤积性肝病。小鼠（Tjp2 cKO 小鼠）中Tjp2的肝脏特异性缺失导致轻度进行性胆汁淤积，而胆血屏障 (BBB) 没有明显退化。这些小鼠更容易受到胆酸 (CA) 诱导的肝损伤。有趣的是，虽然最初也更容易受到影响，但 Tjp2 cKO 小鼠对补充 DDC 的饮食产生了耐受性。DDC 饮食在Tjp2 cKO 小鼠中诱导了一种加剧的导管反应，这是由肝细胞向胆管细胞的转分化引起的。因此，这种转分化只有在Tjp2在肝细胞中失活，但如果在胆管细胞中缺失则不会。Tjp2 cKO 小鼠中 DDC 饮食诱导的肝细胞转分化需要Yap和Wwtr1/Taz，其蛋白质表达在缺乏Tjp2的肝细胞中上调，但与 Notch2 无关。虽然灭活Tjp2足以上调 Yap 和 Wwtr1/Taz 蛋白，但有效的转分化需要 DDC 饮食损伤。因此，Tjp2 负向调节 Yap/Taz 介导的肝细胞向胆管细胞的转分化，以响应 DDC 饮食诱导的肝损伤。此外，转分化在多个水平上受到调节，并且对Tjp2造成的损伤类型肝脏不足在由此产生的病理生理学中起重要作用。