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Lookup NU author(s): Professor Fiona OakleyORCiD, Professor Derek Mann
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
IVA337 is a pan‐peroxisome proliferator‐activated receptor (PPAR) agonist with moderate and well‐balanced activity on the three PPAR isoforms (α, γ, δ). PPARs are regulators of lipid metabolism, inflammation, insulin resistance, and fibrogenesis. Different single or dual PPAR agonists have been investigated for their therapeutic potential in nonalcoholic steatohepatitis (NASH), a chronic liver condition in which steatosis coexists with necroinflammation, potentially leading to liver fibrosis and cirrhosis. Clinical results have demonstrated variable improvements of histologically assessed hepatic lesions depending on the profile of the tested drug, suggesting that concomitant activation of the three PPAR isoforms would translate into a more substantial therapeutic outcome in patients with NASH. We investigated the effects of IVA337 on several preclinical models reproducing the main metabolic and hepatic features associated with NASH. These models comprised a diet‐induced obesity model (high‐fat/high‐sucrose diet); a methionine‐ and choline‐deficient diet; the foz/foz model; the CCl4‐induced liver fibrosis model (prophylactic and therapeutic) and human primary hepatic stellate cells. IVA337 normalized insulin sensitivity while controlling body weight gain, adiposity index, and serum triglyceride increases; it decreased liver steatosis, inflammation, and ballooning. IVA337 demonstrated preventive and curative effects on fibrosis in the CCl4 model and inhibited proliferation and activation of human hepatic stellate cells, the key cells driving liver fibrogenesis in NASH. Moreover, IVA337 inhibited the expression of (pro)fibrotic and inflammasome genes while increasing the expression of β‐oxidation‐related and fatty acid desaturation‐related genes in both the methionine‐ and choline‐deficient diet and the foz/foz model. For all models, IVA337 displayed an antifibrotic efficacy superior to selective PPARα, PPARδ, or PPARγ agonists. Conclusion: The therapeutic potential of IVA337 for the treatment of patients with NASH is supported by our data. (Hepatology Communications 2017;1:524–537)
Author(s): Wettstein G, Luccarini JM, Poekes L, Faye P, Kupkowski F, Adarbes V, Defrêne E, Estivalet C, Gawronski X, Jantzen I, Philippot A, Tessier J, TuyaaBoustugue P, Oakley F, Mann DA, Leclercq I, Francque S, Konstantinova I, Broqua P, Junien JL
Publication type: Article
Publication status: Published
Journal: Hepatology Communications
Year: 2017
Volume: 1
Issue: 6
Pages: 524-537
Print publication date: 02/08/2017
Online publication date: 19/06/2017
Acceptance date: 19/05/2017
Date deposited: 22/02/2019
ISSN (print): 2471-254X
ISSN (electronic): 2471-254X
Publisher: Wiley
URL: https://doi.org/10.1002/hep4.1057
DOI: 10.1002/hep4.1057
PubMed id: 29404476
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