Tags

Type your tag names separated by a space and hit enter

Human hepatic in vitro models reveal distinct anti-NASH potencies of PPAR agonists.
Cell Biol Toxicol. 2020 Jul 01 [Online ahead of print]CB

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.

Authors+Show Affiliations

Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.Department of Urology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium.Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.Department of In Vitro Toxicology and Dermato-Cosmetology, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32613381

Citation

Boeckmans, Joost, et al. "Human Hepatic in Vitro Models Reveal Distinct anti-NASH Potencies of PPAR Agonists." Cell Biology and Toxicology, 2020.
Boeckmans J, Natale A, Rombaut M, et al. Human hepatic in vitro models reveal distinct anti-NASH potencies of PPAR agonists. Cell Biol Toxicol. 2020.
Boeckmans, J., Natale, A., Rombaut, M., Buyl, K., Cami, B., De Boe, V., Heymans, A., Rogiers, V., De Kock, J., Vanhaecke, T., & Rodrigues, R. M. (2020). Human hepatic in vitro models reveal distinct anti-NASH potencies of PPAR agonists. Cell Biology and Toxicology. https://doi.org/10.1007/s10565-020-09544-2
Boeckmans J, et al. Human Hepatic in Vitro Models Reveal Distinct anti-NASH Potencies of PPAR Agonists. Cell Biol Toxicol. 2020 Jul 1; PubMed PMID: 32613381.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Human hepatic in vitro models reveal distinct anti-NASH potencies of PPAR agonists. AU - Boeckmans,Joost, AU - Natale,Alessandra, AU - Rombaut,Matthias, AU - Buyl,Karolien, AU - Cami,Brent, AU - De Boe,Veerle, AU - Heymans,Anja, AU - Rogiers,Vera, AU - De Kock,Joery, AU - Vanhaecke,Tamara, AU - Rodrigues,Robim M, Y1 - 2020/07/01/ PY - 2020/03/24/received PY - 2020/06/17/accepted PY - 2020/7/3/entrez KW - Elafibranor KW - In vitro KW - Non-alcoholic steatohepatitis (NASH) KW - Peroxisome proliferator-activated receptor (PPAR) KW - Pioglitazone KW - Saroglitazar JF - Cell biology and toxicology JO - Cell Biol. Toxicol. N2 - 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. SN - 1573-6822 UR - https://www.unboundmedicine.com/medline/citation/32613381/Human_hepatic_in_vitro_models_reveal_distinct_anti-NASH_potencies_of_PPAR_agonists L2 - https://doi.org/10.1007/s10565-020-09544-2 DB - PRIME DP - Unbound Medicine ER -
Try the Free App:
Prime PubMed app for iOS iPhone iPad
Prime PubMed app for Android
Prime PubMed is provided
free to individuals by:
Unbound Medicine.