Protective functions of ZO-2/Tjp2 expressed in hepatocytes and cholangiocytes against liver injury and cholestasis

• BACKGROUND & AIMS: Liver tight junctions (TJs) establish tissue barriers that isolate bile from the blood circulation. TJP2/ZO-2-inactivating mutations cause progressive cholestatic liver disease in humans. Since the underlying mechanisms remain elusive, we characterized mice with liver-specific inactivation of Tjp2.METHODS: Tjp2 was deleted in hepatocytes, cholangiocytes, or both. Effects on the liver were assessed by biochemical analyses of plasma, liver and bile and .by EM, histology and immunostaining. TJ barrier permeability was evaluated using FITC-Dextran (4kDa). Cholic acid (CA) diet was used to assess susceptibility to liver injury.RESULTS: Liver-specific deletion of Tjp2 resulted in lower Cldn1 protein levels, minor changes to the TJ, dilated canaliculi, lower microvilli density and aberrant Radixin and BSEP distribution, without an overt increase in TJ permeability. Hepatic Tjp2-defcient mice presented with mild progressive cholestasis with lower expression levels of bile acid (BA) transporter Abcb11/Bsep and detoxification enzyme Cyp2b10. A CA-diet tolerated by control mice caused severe cholestasis and liver necrosis in Tjp2-deficient animals. TCPOBOP ameliorated CA-induced injury by enhancing Cyp2b10 expression and ursodeoxycholic acid provided partial improvement. Inactivating Tjp2 separately in hepatocytes or cholangiocytes only showed mild CA-induced liver injury.CONCLUSION: Tjp2 is required for normal cortical distribution of Radixin, canalicular volume regulation and microvilli density, Its inactivation deregulated expression of Cldn1 and key BA transporters and detoxification enzymes. The mice provide a novel animal model for cholestatic liver disease caused by TJP2-inactivating mutations in humans.

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MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Gastroenterologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Gastroenterology and Hepatology (hsv//eng)

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