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Rilpivirine attenuates liver fibrosis through selective STAT1-mediated apoptosis in hepatic stellate cells
  1. Alberto Martí-Rodrigo1,
  2. Fernando Alegre1,2,
  3. Ángela B Moragrega1,
  4. Francisco García-García3,
  5. Pablo Martí-Rodrigo1,
  6. Anabel Fernández-Iglesias4,
  7. Jordi Gracia-Sancho4,5,
  8. Nadezda Apostolova1,
  9. Juan V Esplugues1,2,
  10. Ana Blas-García1
  1. 1Department of Pharmacology, Faculty of Medicine, University of Valencia-CIBERehd, Valencia, Spain
  2. 2FISABIO-Hospital Universitario Dr. Peset, Valencia, Spain
  3. 3Bioinformatics & Biostatistics Unit, Principe Felipe Research Center, Valencia, Spain
  4. 4Liver Vascular Biology Research Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-CIBERehd, Barcelona, Spain
  5. 5Hepatology, Department of Biomedical Research, Inselspital, University of Bern, Bern, Switzerland
  1. Correspondence to Dr Ana Blas-García, Department of Pharmacology, Faculty of Medicine, University of Valencia-CIBERehd, Avenida Blasco Ibáñez, 15-17, Valencia 46010, Spain; ana.blas{at}uv.es

Abstract

Objective Liver 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.

Design The 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.

Results RPV 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.

Conclusion RPV 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.

  • drug repurposing
  • rilpivirine
  • hepatic stellate cells
  • antifibrotic therapy
  • STAT1
  • hepatic regeneration
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Footnotes

  • JVE and AB-G are joint senior authors.

  • Contributors AB-G, AM-R and JVE designed the experiments and analysed the data; AB-G, AM-R, FA, ÁBM, FG-G, PM-R and AF-I performed the experiments; AB-G, JG-S, NA and JVE wrote the manuscript.

  • Funding This work was supported by grants PI14/0312 (from the Fund for Health Research—FIS, co-funded by the European Regional Development Fund of the European Union—'A way to build Europe'), CIBER CB06/04/0071 and EHD19PI03 (both from Instituto de Salud Carlos III, Ministerio de Economia y Competitividad) and by grants SAF2015-67678-R, RTI2018-096748-B-I00 (from Ministerio de Economia y Competitividad, co-funded by the European Regional Development Fund of the European Union) and PROMETEO2018/141 (from Conselleria d'Educació, Investigació, Cultura i Esport, Generalitat Valenciana). AM-R and ÁBM are recipients of Predoctoral Trainee Research Grants (FPU13/00151 and FPU16/05896, respectively; Ministerio de Educación, Cultura y Deporte); AM-R also received a local grant from Fundación Juan Esplugues. MACS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional co-funding from the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA) and the National Institute of Mental Health (NIMH). Targeted supplemental funding for specific projects was also provided by the National Heart, Lung and Blood Institute (NHLBI), and the National Institute on Deafness and Communication Disorders (NIDCD). MACS data collection is also supported by UL1-TR001079 (JHU ICTR) from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research.

  • Disclaimer The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH), Johns Hopkins ICTR or NCATS.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The protocol was approved by the Ethics Committee of Hospital Clínic (Barcelona, Spain) (HCB/2015/0624).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available in a public, open-access repository. All data relevant to the study are included in the article or uploaded as supplementary information.

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