Jing Zhao1,2, Ming Han2, Li Zhou2,3, Pu Liang2, Yun Wang1,2, Shenghu Feng2,4, Hongping Lu2, Xiaoxue Yuan2, Kai Han2, Xiaofan Chen2,5, Shunai Liu2, Jun Cheng6,7,8. 1. Peking University Ditan Teaching Hospital, Beijing, 100015, China. 2. Institiute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China. 3. Department of Infectious Disease, China-Japan Friendship Hospital, Beijing, 100029, China. 4. Department of Infectious Diseases and Clinical Microbiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China. 5. Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing, 100034, China. 6. Peking University Ditan Teaching Hospital, Beijing, 100015, China. chengj0817@sina.cn. 7. Institiute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China. chengj0817@sina.cn. 8. Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University & Capital Medical University, Beijing, 100191, China. chengj0817@sina.cn.
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.
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.
Authors: Alexander Wree; Akiko Eguchi; Matthew D McGeough; Carla A Pena; Casey D Johnson; Ali Canbay; Hal M Hoffman; Ariel E Feldstein Journal: Hepatology Date: 2014-01-30 Impact factor: 17.425
Authors: Elisabeth Karg; Martha Smets; Joel Ryan; Ignasi Forné; Weihua Qin; Christopher B Mulholland; Georgia Kalideris; Axel Imhof; Sebastian Bultmann; Heinrich Leonhardt Journal: J Mol Biol Date: 2017-10-18 Impact factor: 5.469
Authors: Florian Hladik; Adam Burgener; Lamar Ballweber; Raphael Gottardo; Lucia Vojtech; Slim Fourati; James Y Dai; Mark J Cameron; Johanna Strobl; Sean M Hughes; Craig Hoesley; Philip Andrew; Sherri Johnson; Jeanna Piper; David R Friend; T Blake Ball; Ross D Cranston; Kenneth H Mayer; M Juliana McElrath; Ian McGowan Journal: Elife Date: 2015-02-03 Impact factor: 8.713