Regulation of hepatic stellate cell contraction and cirrhotic portal hypertension by Wnt/β-catenin signalling via interaction with Gli1.

Tytuł:: Regulation of hepatic stellate cell contraction and cirrhotic portal hypertension by Wnt/β-catenin signalling via interaction with Gli1.
Autorzy:: Zhang F; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Wang F; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
He J; The Third Institute of Oceanography, Ministry of Natural Resources, Xiamen, China.
Lian N; School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
Wang Z; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Shao J; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Ding H; Department of Integrated TCM & Western Medicine in Hepatology, The Nanjing Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, China.
Tan S; Department of Integrated TCM & Western Medicine in Hepatology, The Nanjing Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, China.
Chen A; Department of Pathology, School of Medicine, Saint Louis University, St. Louis, Missouri, USA.
Zhang Z; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Wang S; Shandong Co-innovation Center of TCM Formula, College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
Zheng S; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Źródło:: British journal of pharmacology [Br J Pharmacol] 2021 Jun; Vol. 178 (11), pp. 2246-2265. Date of Electronic Publication: 2021 Apr 14.
Typ publikacji:: Journal Article; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Publication: London : Wiley
Original Publication: London, Macmillian Journals Ltd.
MeSH Terms:: Hepatic Stellate Cells*
Hypertension, Portal*/pathology
Wnt Signaling Pathway*
Zinc Finger Protein GLI1*
Animals ; Cell Line ; Humans ; Liver Cirrhosis/pathology ; Mice ; Transcription Factor 4
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Grant Information:: 81870423 National Natural Science Foundation of China; 82073914 National Natural Science Foundation of China; 31401210 National Natural Science Foundation of China; 19KJA310005 Major Project of the Natural Science Research of Jiangsu Higher Education Institutions; JKLPSE202005 Open Project of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica; JKLPSE201815 Open Project of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica; JKLPSE201804 Open Project of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica; Priority Academic Program Development of Jiangsu Higher Education Institutions; 2018020 Scientific Research Foundation of Third Institute of Oceanography of Ministry of Natural Resources; 2017Y0061 Science and Technology Plan Program of Fujian Province; 16CZP012SF04 Xiamen Marine Economic Innovation and Development Demonstration Project
Contributed Indexing:: Keywords: Gli1; Sufu; Wnt; contraction; hepatic stellate cell; portal hypertension; β-catenin
Substance Nomenclature:: 0 (GLI1 protein, human)
0 (Gli1 protein, mouse)
0 (TCF4 protein, human)
0 (Tcf4 protein, mouse)
0 (Transcription Factor 4)
0 (Zinc Finger Protein GLI1)
Entry Date(s):: Date Created: 20201021 Date Completed: 20210705 Latest Revision: 20220531
Update Code:: 20240105
DOI:: 10.1111/bph.15289
PMID:: 33085791
: Czasopismo naukowe

Pełny tekst

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.
(© 2020 The British Pharmacological Society.)

Comment in: Br J Pharmacol. 2021 Jan;178(2):378-380. (PMID: 33085773)

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