Implication of autophagy in the antifibrogenic effect of Rilpivirine: when more is less


Por: Lucantoni F, Benedicto AM, Gruevska A, Moragrega ÁB, Fuster-Martínez I, Esplugues JV, Blas-García A and Apostolova N

Publicada: 20 abr 2022 Ahead of Print: 20 abr 2022
Resumen:
As the main extracellular matrix-producing cells, activated hepatic stellate cells (HSC) are fundamental mediators of liver fibrosis (LF), and understanding their activation/inactivation mechanisms is paramount to the search for novel therapeutics. The antiretroviral drug Rilpivirine (RPV) has demonstrated a hepatoprotective effect in several animal models of chronic liver injury that is related to its antifibrogenic and apoptotic action in HSC. In the present study, we evaluated whether autophagy is implicated in the hepatoprotective action of RPV, as autophagy plays an important role in HSC transdifferentiation. We employed two standard mouse models of chronic liver injury - fatty liver disease and carbon tetrachloride (CCl4)-induced hepatotoxicity -and cultured HSC activated with the profibrotic cytokine TGF-beta. RPV enhanced autophagy in the whole liver of both mouse models and in activated HSC, evident in the protein expression of autophagy markers, increased autophagosome content and lysosomal mass. Moreover, increased autophagic flux was observed in RPV-exposed HSC as revealed by tandem fluorescence-tagged LC3 and p62 and analysis of LC3-II accumulation in cells exposed to the lysosomal inhibitor chloroquine. Importantly, autophagy was involved in the cytotoxic effect of RPV on HSC, though in a differential manner. Pharmacological inhibition of autophagy by 3-methyladenine (3-MA) did not affect the diminishing effect of RPV on viability, while treatment with wortmannin or depletion of specific autophagy proteins (ATG5, Beclin-1 and SQSTM1/p62) rescued the detrimental effect of high concentrations of RPV on the viability of activated HSC. Finally, we also provide evidence that RPV compromises the viability of TGF-beta-induced HSC independently of its antifibrogenic effect, observed as reduced collagen 1A1 synthesis, and that this effect does not include RPV ' s modulation of autophagy. In summary, as a contributor to the mechanisms involved in the hepatoprotective action of RPV, autophagy may be a good candidate to explore when developing novel therapeutics for LF.

Filiaciones:
:
 Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain

 FISABIO-Hospital Universitario Dr. Peset, Valencia, Spain

Benedicto AM:
 Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain

:
 Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain

 FISABIO-Hospital Universitario Dr. Peset, Valencia, Spain

:
 Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain

 FISABIO-Hospital Universitario Dr. Peset, Valencia, Spain

Fuster-Martínez I:
 Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain

:
 Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain

 FISABIO-Hospital Universitario Dr. Peset, Valencia, Spain

 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Valencia, Spain

:
 FISABIO-Hospital Universitario Dr. Peset, Valencia, Spain

 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Valencia, Spain

 Departamento de Fisiología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain

:
 Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.

 FISABIO-Hospital Universitario Dr. Peset, Valencia, Spain.

 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Valencia, Spain.
ISSN: 20414889





CELL DEATH & DISEASE
Editorial
Nature Publishing Group, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND, Reino Unido
Tipo de documento: Article
Volumen: 13 Número: 4
Páginas: 385-385
WOS Id: 000786510400003
ID de PubMed: 35443746
imagen Green Published, gold

FULL TEXT

imagen Published Version
No Accesible

MÉTRICAS