Rilpivirine attenuates liver fibrosis through selective STAT1-mediated apoptosis in hepatic stellate cells

• Published in: Gut Vol. 69; no. 5; pp. 920 - 932
• Main Authors: Martí-Rodrigo, Alberto, Alegre, Fernando, Moragrega, Ángela B, García-García, Francisco, Martí-Rodrigo, Pablo, Fernández-Iglesias, Anabel, Gracia-Sancho, Jordi, Apostolova, Nadezda, Esplugues, Juan V, Blas-García, Ana
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.05.2020
• Subjects: Animal models; Antiretroviral drugs; Apoptosis; Bile; Bile ducts; Carbon tetrachloride; Cell culture; Cell lines; Cytokines; Experiments; Extracellular matrix; Fatty liver; FDA approval; Fibrosis; Gene expression; Hepatocytes; Hepatotoxicity; HIV; Human immunodeficiency virus; Inflammation; Interleukin 6; Janus kinase; Kinases; Laboratory animals; Lipids; Liver diseases; Molecular modelling; Proteins; Signal transduction; Stat1 protein; Stat3 protein; Steatosis; Stellate cells; Therapeutic applications; Transcription; United States > US; Spain; hepatic regeneration; hepatic stellate cells; antifibrotic therapy; drug repurposing; STAT1; rilpivirine
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gutjnl-2019-318372

ObjectiveLiver fibrosis constitutes a major health problem worldwide due to its rapidly increasing prevalence and the lack of specific and effective treatments. Growing evidence suggests that signalling through cytokine-activated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways regulates liver fibrosis and regeneration. Rilpivirine (RPV) is a widely used anti-HIV drug not reported to produce hepatotoxicity. We aimed to describe the potential hepatoprotective effects of RPV in different models of chronic liver injury, focusing on JAK-STAT signalling regulation.DesignThe effects of RPV on hepatic steatosis, inflammation and fibrogenesis were studied in a nutritional mouse model of non-alcoholic fatty liver disease, carbon tetrachloride-induced fibrosis and bile duct ligation-induced fibrosis. Primary human hepatic stellate cells (hHSC) and human cell lines LX-2 and Hep3B were used to investigate the underlying molecular mechanisms.ResultsRPV exerted a clear anti-inflammatory and antifibrotic effect in all the in vivo models of liver injury employed, and enhanced STAT3-dependent proliferation in hepatocytes and apoptosis in HSC through selective STAT1 activation. These results were reproduced in vitro; RPV undermined STAT3 activation and triggered STAT1-mediated pathways and apoptosis in HSC. Interestingly, this selective pro-apoptotic effect completely disappeared when STAT1 was silenced. Conditioned medium experiments showed that HSC apoptosis activated STAT3 in hepatocytes in an interleukin-6-dependent mechanism.ConclusionRPV ameliorates liver fibrosis through selective STAT1-dependent induction of apoptosis in HSC, which exert paracrinal effects in hepatocytes, thus promoting liver regeneration. RPV’s actions may represent an effective strategy to treat chronic liver diseases of different aetiologies and help identify novel therapeutic targets.