Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 14, 2023; 29(18): 2798-2817
Published online May 14, 2023. doi: 10.3748/wjg.v29.i18.2798
Calcitriol attenuates liver fibrosis through hepatitis C virus nonstructural protein 3-transactivated protein 1-mediated TGF β1/Smad3 and NF-κB signaling pathways
Liu Shi, Li Zhou, Ming Han, Yu Zhang, Yang Zhang, Xiao-Xue Yuan, Hong-Ping Lu, Yun Wang, Xue-Liang Yang, Chen Liu, Jun Wang, Pu Liang, Shun-Ai Liu, Xiao-Jing Liu, Jun Cheng, Shu-Mei Lin
Liu Shi, Xiao-Jing Liu, Shu-Mei Lin, Department of Infectious Disease Medicine, The First Hospital Affiliated to Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
Li Zhou, China-Japan Friendship Hospital, Department of Infectious Disease China-Japan Friendship Hospital, Beijing 100029, China
Ming Han, Yang Zhang, Xiao-Xue Yuan, Chen Liu, Pu Liang, Shun-Ai Liu, Jun Cheng, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
Yu Zhang, Yun Wang, The Division of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
Hong-Ping Lu, Institute of Liver Diseases, Beijing Pan-Asia Tongze Institute of Biomedicine Co., Ltd, Beijing 100015, China
Xue-Liang Yang, Department of Rehabilitation Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
Jun Wang, Beijing Key Laboratory of Emerging Infectious Diseases, Peking University Ditan Teaching Hospital, Beijing 100015, China
Author contributions: Shi L, Zhou L, Han M, Zhang Y, Zhang Y, Yuan XX, Lu HP, Wang Y, Yang XL, Liu C, Wang J, Liang P, Liu SA, Liu XJ, Cheng J, and Lin SM contributed to the study conception and design; Liu S, Li Z, Ming H, Yu Z, Yang Z, Xue YX, Ping LH, Yun W, Liang YX, Chen L, Jun W, and Jing LX participated in the design and completion of the experiment; Liu S wrote the original draft; Liu S, Jun C, and Mei LS reviewed and edited the manuscript; Pu L and Ai LS finished the project administration; Jun C and Mei LS have the same contribution to the article; all authors approved the final version of the article.
Supported by the National Key Research and Development Program of China, No. 2017YFC0908104; and National Science and Technology Projects, No. 2017ZX10203201, No. 2017ZX10201201, and No. 2017ZX10202202.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee at Xi’an Jiaotong University Medical Science Center (approval No. 2020-1739).
Conflict-of-interest statement: The authors declare that they have no competing interests.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Shu-Mei Lin, Doctor, MD, PhD, Doctor, Professor, Teacher, Department of Infectious Disease Medicine, The First Hospital Affiliated to Xi’an Jiaotong University, No. 277 Yanta West Road, Yanta, Xi’an 710061, Shaanxi Province, China.
Received: December 13, 2022
Peer-review started: December 13, 2022
First decision: February 23, 2023
Revised: March 8, 2023
Accepted: April 10, 2023
Article in press: April 10, 2023
Published online: May 14, 2023
Research background

Despite the lack of a specific therapeutic medicine, liver fibrosis still constitutes a serious hazard to human health, hence it is critical to identify novel targets for its therapy. After screening using suppressive subtractive hybridization and bioinformatics analysis, our research team discovered that hepatitis C virus nonstructural protein 3-transactivated protein 1 (NS3TP1) may be involved in the occurrence of liver fibrosis. As a result, the role of NS3TP1 in liver fibrosis was investigated to provide a new target for the treatment of liver fibrosis.

Research motivation

A potential new target for the treatment of hepatic fibrosis is provided by this work.

Research objectives

To determine whether NS3TP1 can promote liver fibrosis and whether calcitriol can inhibit the occurrence of liver fibrosis through NS3TP1.

Research methods

In vitro experiments were performed on carbon tetrachloride mouse liver, and NS3TP1 and fibrosis-related indexes were studied through serological and pathological tests. In vivo experiments were performed on LX-2 cells, and siRNA-NS3TP1 and pcDNA-NS3TP1 were constructed and transfected into LX-2 cells, respectively. Collagen I, collagen III, α-smooth muscle actin (α-SMA), TGFβ1/Smad3 and NF-κB signaling pathways were detected by western blot, RT-PCR, Co-imunoprecipitation and luciferase assays.

Research results

Collagen I, collagen III, α-SMA, transforming growth factor beta (TGFβ1)/Smad3, and NF-κB signaling pathways were found to be up-regulated following overexpression of NS3TP1, whereas the aforementioned indices were shown to be down-regulated after NS3TP1 interference in vitro. Results from Co-IP and Luciferase assays confirmed that Smad3 and p65 could both bind to NS3TP1, and that p65 boosted NS3TP1’s promoter activity while NS3TP1 increased the promoter activity of TGFβ receptor I (TGFβ-RI). NS3TP1 and fibrosis-related indicators decreased after calcitriol therapy both in vitro and in vivo, and calcitriol restrained the expression of TGFβ1/Smad3 and NF-κB signaling pathways via NS3TP1.

Research conclusions

NS3TP1 promotes hepatic fibrosis through TGFβ1/Smad3 and NF-κB signaling pathways. Calcitriol further inhibits TGFβ1/Smad3 and NF-κB signaling pathways to reduce liver fibrosis by down-regulating NS3TP1.

Research perspectives

NS3TP1 provides a novel target for the treatment of liver fibrosis and a direction for the research of potential drug targets. Calcitriol is endowed with new functions as an adjunct therapeutic drug for liver fibrosis.