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β‐catenin Conditional Knockout Plays a Protective Role in Lithocholic Acid Induced Murine Model of Cholestatic Liver Injury
Author(s) -
Goel Chhavi,
Zhang Rong,
Cornuet Pamela,
Ma Xiaochao,
NejakBowen Kari
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.05382
Subject(s) - lithocholic acid , liver injury , cholestasis , multidrug resistance associated protein 2 , bile acid , knockout mouse , immunostaining , medicine , endocrinology , chemistry , biology , transporter , biochemistry , immunohistochemistry , atp binding cassette transporter , receptor , gene
Study Objective To investigate if liver‐specific β‐catenin knockdown could mitigate development of cholestatic liver injury in lithocholic acid (LCA)‐supplemented diet model and understand the underlying mechanism(s) of protection. Hypothesis We recently showed that loss or inhibition of liver specific β‐catenin confers protection and prevents the development of cholestatic liver injury after bile duct ligation (BDL). Since, bile acid (BA) accumulation is the causal factor for both BDL and LCA induced cholestatic injury, we hypothesized that β‐catenin conditional knockout would provide protection from LCA‐induced injury as well. Methods Age‐matched wild‐type control (Con) and β‐catenin liver‐specific knockout (KO) mice were fed 0.6% LCA diet for 7 days and then euthanized. Liver histology and serum biochemistry were done for fibrosis and parameters of cholestatic injury. Immunostaining and relative gene expression was assessed to analyze ductular response and regulatory bile detoxifying enzymes and transporters. Liquid chromatography‐mass spectrometry was performed to determine BA species. Results KO mice showed fewer and smaller necrotic areas as compared to Con mice after LCA‐diet. Serum biochemistry showed significant decrease in biliary injury in KO mice. Although total liver BA levels were comparable, serum BA was decreased in KO. Pan‐cytokeratin immunostaining showed increased ductular response in KO, suggesting a defense response for mediating enhanced BA clearance. Analysis of BA homeostasis and transport genes showed that KO had decreased BA uptake transporters, increased apical and basolateral efflux transporters, and increased expression of detoxifying cytochrome P450 enzymes, resulting in overall decreased accumulation of toxic BA in the liver. Analyzing the BA composition showed comparable hydrophobicity index in KO and Con, however, altered BA composition in KO after LCA‐diet was observed with a predominance of TbMCA over TMDCA, a known secondary BA. Conclusions β‐catenin conditional knockout improves the overall outcome and confers protection from LCA‐induced cholestatic liver injury, similar to that observed after BDL in our previous findings. This is achieved through increased BA transporters, hydroxylation of toxic BA and enhanced ductular proliferation to improve BA clearance. Further investigations would be focused on assessing the role of hepatocyte‐specific β‐catenin knockdown in eliciting similar protection from injury or disease severity after LCA administration.