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Cell Biol Toxicol ; 37(2): 293-311, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-32613381

RESUMEN

Non-alcoholic steatohepatitis (NASH) is a highly prevalent, chronic liver disease characterized by hepatic lipid accumulation, inflammation, and concomitant fibrosis. Up to date, no anti-NASH drugs have been approved. In this study, we reproduced key NASH characteristics in vitro by exposing primary human hepatocytes (PHH), human skin stem cell-derived hepatic cells (hSKP-HPC), HepaRG and HepG2 cell lines, as well as LX-2 cells to multiple factors that play a role in the onset of NASH. The obtained in vitro disease models showed intracellular lipid accumulation, secretion of inflammatory chemokines, induced ATP content, apoptosis, and increased pro-fibrotic gene expression. These cell systems were then used to evaluate the anti-NASH properties of eight peroxisome proliferator-activated receptor (PPAR) agonists (bezafibrate, elafibranor, fenofibrate, lanifibranor, pemafibrate, pioglitazone, rosiglitazone, and saroglitazar). PPAR agonists differently attenuated lipid accumulation, inflammatory chemokine secretion, and pro-fibrotic gene expression.Based on the obtained readouts, a scoring system was developed to grade the anti-NASH potencies. The in vitro scoring system, based on a battery of the most performant models, namely PHH, hSKP-HPC, and LX-2 cultures, showed that elafibranor, followed by saroglitazar and pioglitazone, induced the strongest anti-NASH effects. These data corroborate available clinical data and show the relevance of these in vitro models for the preclinical investigation of anti-NASH compounds.


Asunto(s)
Hígado/patología , Modelos Biológicos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Receptores Activados del Proliferador del Peroxisoma/agonistas , Quimiocinas/metabolismo , Niño , Preescolar , Regulación de la Expresión Génica , Células Hep G2 , Humanos , Mediadores de Inflamación/metabolismo , Lipogénesis , Enfermedad del Hígado Graso no Alcohólico/patología , Piel/citología , Factores de Transcripción/metabolismo
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