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Regulation of hepatic stellate cell contraction and cirrhotic portal hypertension by Wnt/β‐catenin signalling via interaction with Gli1
Author(s) -
Zhang Feng,
Wang Feixia,
He Jianlin,
Lian Naqi,
Wang Zhenyi,
Shao Jiangjuan,
Ding Hai,
Tan Shanzhong,
Chen Anping,
Zhang Zili,
Wang Shijun,
Zheng Shizhong
Publication year - 2021
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15289
Subject(s) - wnt signaling pathway , hepatic stellate cell , cancer research , biology , beta catenin , gli1 , microbiology and biotechnology , catenin , hedgehog signaling pathway , signal transduction , endocrinology , chemistry
Background and Purpose Portal hypertension is a lethal complication of cirrhosis. Its mechanism and therapeutic targets remain largely unknown. Hepatic stellate cell (HSC) contraction increases intrahepatic vascular resistance contributing to portal hypertension. We investigated how HSC contraction was regulated by Wnt signalling and the therapeutic implications. Experimental Approach Liver tissues from cirrhotic patients were examined. Cirrhotic mice with genetic or pharmacological treatments were used for in vivo assessments, and their primary cells were isolated. Cellular functions and signalling pathways were analysed in human HSC‐LX2 cells using real‐time PCR, Western blotting, siRNA, luciferase reporter assay, chromatin immunoprecipitation, co‐immunoprecipitation and site‐directed mutagenesis. Key Results Wnt/β‐catenin correlated with HSC contraction in human cirrhotic liver. Wnt3a stimulated Smo‐independent Gli1 nuclear translocation followed by LARG‐mediated RhoA activation leading to HSC contraction. Suppressor of fused (Sufu) negatively mediated Wnt3a‐induced Gli1 nuclear translocation. Wnt/β‐catenin repressed transcription of Sufu dependent on β‐catenin/TCF4 interaction and TCF4 binding to Sufu promoter. Molecular simulation and site‐directed mutagenesis identified the β‐catenin residues Lys312 and Lys435 critically involved in this interaction. TCF4 binding to the sequence CACACCTTCC at Sufu promoter was required for transrepression of Sufu. In cirrhotic mice, short‐term liver‐targeting β‐catenin deficiency or acute treatment with β‐catenin inhibitors reduced portal pressure via restriction of HSC contraction rather than inhibiting HSC activation. Long‐term deficiency or treatments also ameliorated liver injury, fibrosis and inflammation. Conclusion and Implications Interaction between Wnt/β‐catenin and Smo‐independent Gli1 pathways promoted HSC contraction via TCF4‐dependent transrepression of Sufu. HSC‐specific inhibition of β‐catenin may have therapeutic benefits for cirrhotic portal hypertension.