Jianliang Xu1, P Jaya Kausalya1, Noémi Van Hul2, Matias J Caldez2, Shiyi Xu1, Alicia Ghia Min Ong1, Wan Lu Woo1, Safiah Mohamed Ali1, Philipp Kaldis3, Walter Hunziker4. 1. Epithelial Polarity in Disease and Tissue Regeneration Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A∗STAR), Singapore. 2. Cell Division and Cancer Research Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A∗STAR), Singapore. 3. Cell Division and Cancer Research Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A∗STAR), Singapore; Lund University, Department of Clinical Sciences, Clinical Research Centre, Malmö, Sweden. 4. Epithelial Polarity in Disease and Tissue Regeneration Laboratory, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A∗STAR), Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address: hunziker@imcb.a-star.edu.sg.
Abstract
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. Because 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 electron microscopy, histology, and immunostaining. TJ barrier permeability was evaluated using fluorescein isothiocyanate-dextran (4 kDa). 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 bile salt export pump (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 transporter Abcb11/Bsep and detoxification enzyme Cyp2b10. A CA diet tolerated by control mice caused severe cholestasis and liver necrosis in Tjp2-deficient animals. 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene ameliorated CA-induced injury by enhancing Cyp2b10 expression, and ursodeoxycholic acid provided partial improvement. Inactivating Tjp2 separately in hepatocytes or cholangiocytes showed only 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 bile acid transporters and detoxification enzymes. The mice provide a novel animal model for cholestatic liver disease caused by TJP2-inactivating mutations in humans.
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. Because 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 electron microscopy, histology, and immunostaining. TJ barrier permeability was evaluated using fluorescein isothiocyanate-dextran (4 kDa). 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 bile salt export pump (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 transporter Abcb11/Bsep and detoxification enzyme Cyp2b10. A CA diet tolerated by control mice caused severe cholestasis and liver necrosis in Tjp2-deficient animals. 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene ameliorated CA-induced injury by enhancing Cyp2b10 expression, and ursodeoxycholic acid provided partial improvement. Inactivating Tjp2 separately in hepatocytes or cholangiocytes showed only 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 bile acid transporters and detoxification enzymes. The mice provide a novel animal model for cholestatic liver disease caused by TJP2-inactivating mutations in humans.
Authors: Chao Zheng Li; Hiromi Ogawa; Soon Seng Ng; Xindi Chen; Eriko Kishimoto; Kokoro Sakabe; Aiko Fukami; Yueh-Chiang Hu; Christopher N Mayhew; Jennifer Hellmann; Alexander Miethke; Nahrin L Tasnova; Samuel J I Blackford; Zu Ming Tang; Adam M Syanda; Liang Ma; Fang Xiao; Melissa Sambrotta; Oliver Tavabie; Filipa Soares; Oliver Baker; Davide Danovi; Hisamitsu Hayashi; Richard J Thompson; S Tamir Rashid; Akihiro Asai Journal: JHEP Rep Date: 2022-02-01
Authors: Jianliang Xu; P Jaya Kausalya; Alicia Ghia Min Ong; Christine Meng Fan Goh; Safiah Mohamed Ali; Walter Hunziker Journal: NPJ Regen Med Date: 2022-09-23