1. Academic Validation
  2. Human hepatic in vitro models reveal distinct anti-NASH potencies of PPAR agonists

Human hepatic in vitro models reveal distinct anti-NASH potencies of PPAR agonists

  • Cell Biol Toxicol. 2021 Apr;37(2):293-311. doi: 10.1007/s10565-020-09544-2.
Joost Boeckmans 1 Alessandra Natale 1 Matthias Rombaut 1 Karolien Buyl 1 Brent Cami 1 Veerle De Boe 2 Anja Heymans 1 Vera Rogiers 1 Joery De Kock 1 Tamara Vanhaecke  # 1 Robim M Rodrigues  # 3
Affiliations

Affiliations

  • 1 Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
  • 2 Department of Urology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium.
  • 3 Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium. Robim.Marcelino.Rodrigues@vub.be.
  • # Contributed equally.
Abstract

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.

Keywords

Elafibranor; In vitro; Non-alcoholic steatohepatitis (NASH); Peroxisome proliferator-activated receptor (PPAR); Pioglitazone; Saroglitazar.

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