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

Xu, Jianliang ; Kausalya, P Jaya ; Van Hul, Noémi ; Caldez, Matias J ; Xu, Shiyi ; Min Ong, Alicia Ghia ; Woo, Wan Lu ; Ali, Safiah Mohamed ; Kaldis, Philipp LU orcid and Hunziker, Walter (2021) In Gastroenterology 160(6). p.2103-2118
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. 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... (More)

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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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Gastroenterology
volume
160
issue
6
pages
2103 - 2118
publisher
Elsevier
external identifiers
  • scopus:85104915893
  • pmid:33465371
ISSN
1528-0012
DOI
10.1053/j.gastro.2021.01.027
language
English
LU publication?
yes
id
5152b011-e4a1-4154-9a8b-d0e8a25ed331
date added to LUP
2021-01-25 09:51:21
date last changed
2024-03-21 01:16:25
@article{5152b011-e4a1-4154-9a8b-d0e8a25ed331,
  abstract     = {{<p>BACKGROUND &amp; 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.</p><p>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.</p><p>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.</p><p>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.</p>}},
  author       = {{Xu, Jianliang and Kausalya, P Jaya and Van Hul, Noémi and Caldez, Matias J and Xu, Shiyi and Min Ong, Alicia Ghia and Woo, Wan Lu and Ali, Safiah Mohamed and Kaldis, Philipp and Hunziker, Walter}},
  issn         = {{1528-0012}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{6}},
  pages        = {{2103--2118}},
  publisher    = {{Elsevier}},
  series       = {{Gastroenterology}},
  title        = {{Protective functions of ZO-2/Tjp2 expressed in hepatocytes and cholangiocytes against liver injury and cholestasis}},
  url          = {{http://dx.doi.org/10.1053/j.gastro.2021.01.027}},
  doi          = {{10.1053/j.gastro.2021.01.027}},
  volume       = {{160}},
  year         = {{2021}},
}