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01-01-2020 | Original Article

TAF and TDF attenuate liver fibrosis through NS5ATP9, TGFβ1/Smad3, and NF-κB/NLRP3 inflammasome signaling pathways

Authors: Jing Zhao, Ming Han, Li Zhou, Pu Liang, Yun Wang, Shenghu Feng, Hongping Lu, Xiaoxue Yuan, Kai Han, Xiaofan Chen, Shunai Liu, Jun Cheng

Published in: Hepatology International | Issue 1/2020

Abstract

Background

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

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/NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome 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/NLRP3 inflammasome 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 marginal 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/NLRP3 inflammasome 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.

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Title: TAF and TDF attenuate liver fibrosis through NS5ATP9, TGFβ1/Smad3, and NF-κB/NLRP3 inflammasome signaling pathways
Authors: Jing Zhao
Ming Han
Li Zhou
Pu Liang
Yun Wang
Shenghu Feng
Hongping Lu
Xiaoxue Yuan
Kai Han
Xiaofan Chen
Shunai Liu
Jun Cheng
Publication date: 01-01-2020
Publisher: Springer India
Published in: Hepatology International / Issue 1/2020
Print ISSN: 1936-0533
Electronic ISSN: 1936-0541
DOI: https://doi.org/10.1007/s12072-019-09997-6

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Abstract

Background

Methods

Results

Conclusions

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Abstract

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