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TAF and TDF Attenuate Liver Fibrosis through NS5ATP9, TGFβ1/Smad3, and NF-κB Signaling Pathways

28 Pages Posted: 22 Dec 2018

See all articles by Jing Zhao

Jing Zhao

Peking University

Ming Han

Peking University

Li Zhou

Beijing Key Laboratory of Emerging Infectious Diseases

Shunai Liu

Beijing Key Laboratory of Emerging Infectious Diseases

Yun Wang

Peking University

Shenghu Feng

Beijing Key Laboratory of Emerging Infectious Diseases

Hongping Lu

Beijing Key Laboratory of Emerging Infectious Diseases

Xiaoxue Yuan

Beijing Key Laboratory of Emerging Infectious Diseases

Kai Han

Beijing Key Laboratory of Emerging Infectious Diseases

Xiaofan Chen

Beijing Key Laboratory of Emerging Infectious Diseases

Pu Liang

Beijing Key Laboratory of Emerging Infectious Diseases

Jun Cheng

Beijing Key Laboratory of Emerging Infectious Diseases; Capital Medical University - Institute of Infectious Diseases

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Abstract

Objective: This study aimed to investigate the roles and mechanisms of action of tenofovir alafenamide fumarate (TAF)/tenofovir disoproxil fumarate (TDF) in liver fibrosis treatment.

Methods: The effects of TAF/TDF on carbon tetrachloride (CCl4)-induced liver fibrosis in C57BL/6 wild-type or nonstructural protein 5A transactivated protein 9 (NS5ATP9) knockout mice were studied. The differentiation, activation, and proliferation of LX-2 cells after TAF/TDF treatment were tested in vitro. The expression of NS5ATP9 and activities of transforming growth factor-β1 (TGFβ1)/sekelsky mothers against Decapentaplegic Homolog 3 (Smad3) and NF-κB signaling pathways were detected in TAF/TDF-treated mice and LX-2 cells. The genes related to extracellular matrix accumulation were detected in vivo and in vitro after NS5ATP9 silencing or knockout.

Results: TAF/TDF significantly inhibited CCl4-induced liver fibrosis in mice and regulated the differentiation, activation, and proliferation of hepatic stellate cells (HSCs). Furthermore, TAF/TDF suppressed the activities of TGFβ1/Smad3 and NF-κB signaling pathways in vivo and in vitro. NS5ATP9 inhibited liver fibrosis through TGFβ1/Smad3 and NF-κB signaling pathways. TAF/TDF upregulated the expression of NS5ATP9 in vivo and in vitro. Finally, TAF/TDF could only show marginly therapeutic effects when NS5ATP9 was silenced and knocked out in vivo and in vitro.

Conclusions: TAF/TDF prevented progression and promoted reversion of liver fibrosis through assembling TGFβ1/Smad3 and NF-κB signaling pathways via upregulating the expression of NS5ATP9. TAF/TDF also regulated the differentiation, activation, and proliferation of HSCs. The findings provided strong evidence for the role of TAF/TDF as a new promising therapeutic strategy in liver fibrosis.

Funding Statement: This study was supported by the National Natural Science Foundation of China (No. 81470863 and No. 81670547), the National Key Research and Development Program of China (No. 2017YFC0908100 and No. 2017YFC0908104), the Beijing Municipal Administration of Hospitals (XMLX201711 to JC), the Beijing Municipal Administration of Hospitals’ Ascent Plan (DFL20151701), and the National Science and Technology Major Project 2017ZX10201201-002-004). Support was also provided by the Collaborative Innovation Center of Infectious Diseases and the Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.

Declaration of Interests: The authors declare no competing interests.

Ethics Approval Statement: All animal experiments were conducted according to the ethical rules.

Keywords: Liver fibrosis, NS5ATP9, TAF/TDF

Suggested Citation

Zhao, Jing and Han, Ming and Zhou, Li and Liu, Shunai and Wang, Yun and Feng, Shenghu and Lu, Hongping and Yuan, Xiaoxue and Han, Kai and Chen, Xiaofan and Liang, Pu and Cheng, Jun, TAF and TDF Attenuate Liver Fibrosis through NS5ATP9, TGFβ1/Smad3, and NF-κB Signaling Pathways (July 12, 2018). Available at SSRN: https://ssrn.com/abstract=3299128

Jing Zhao

Peking University

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Ming Han

Peking University

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Li Zhou

Beijing Key Laboratory of Emerging Infectious Diseases

Beijing, 100015
China

Shunai Liu

Beijing Key Laboratory of Emerging Infectious Diseases

Beijing, 100015
China

Yun Wang

Peking University

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Shenghu Feng

Beijing Key Laboratory of Emerging Infectious Diseases

Beijing, 100015
China

Hongping Lu

Beijing Key Laboratory of Emerging Infectious Diseases

Beijing, 100015
China

Xiaoxue Yuan

Beijing Key Laboratory of Emerging Infectious Diseases

Beijing, 100015
China

Kai Han

Beijing Key Laboratory of Emerging Infectious Diseases

Beijing, 100015
China

Xiaofan Chen

Beijing Key Laboratory of Emerging Infectious Diseases

Beijing, 100015
China

Pu Liang

Beijing Key Laboratory of Emerging Infectious Diseases

Beijing, 100015
China

Jun Cheng (Contact Author)

Beijing Key Laboratory of Emerging Infectious Diseases ( email )

Beijing, 100015
China

Capital Medical University - Institute of Infectious Diseases ( email )

Beijing, 100015
China

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