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The new-generation pan-peroxisome proliferator-activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis.
Hepatol Commun. 2017 08; 1(6):524-537.HC

Abstract

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).

Authors+Show Affiliations

Inventiva Daix France.Inventiva Daix France.Pôle d'Hépato-gastro-entérologie, Université Catholique de Louvain Bruxelles Belgium.Inventiva Daix France.Inventiva Daix France.Inventiva Daix France.Inventiva Daix France.Inventiva Daix France.Inventiva Daix France.Inventiva Daix France.Inventiva Daix France.Inventiva Daix France.Inventiva Daix France.Medical School, Newcastle University Newcastle United Kingdom.Medical School, Newcastle University Newcastle United Kingdom.Pôle d'Hépato-gastro-entérologie, Université Catholique de Louvain Bruxelles Belgium.Antwerp University Hospital, Gastroenterology and Hepatology Antwerp Belgium.Inventiva Daix France.Inventiva Daix France.Inventiva Daix France.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29404476

Citation

Wettstein, Guillaume, et al. "The New-generation Pan-peroxisome Proliferator-activated Receptor Agonist IVA337 Protects the Liver From Metabolic Disorders and Fibrosis." Hepatology Communications, vol. 1, no. 6, 2017, pp. 524-537.
Wettstein G, Luccarini JM, Poekes L, et al. The new-generation pan-peroxisome proliferator-activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis. Hepatol Commun. 2017;1(6):524-537.
Wettstein, G., Luccarini, J. M., Poekes, L., Faye, P., Kupkowski, F., Adarbes, V., Defrêne, E., Estivalet, C., Gawronski, X., Jantzen, I., Philippot, A., Tessier, J., Tuyaa-Boustugue, P., Oakley, F., Mann, D. A., Leclercq, I., Francque, S., Konstantinova, I., Broqua, P., & Junien, J. L. (2017). The new-generation pan-peroxisome proliferator-activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis. Hepatology Communications, 1(6), 524-537. https://doi.org/10.1002/hep4.1057
Wettstein G, et al. The New-generation Pan-peroxisome Proliferator-activated Receptor Agonist IVA337 Protects the Liver From Metabolic Disorders and Fibrosis. Hepatol Commun. 2017;1(6):524-537. PubMed PMID: 29404476.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The new-generation pan-peroxisome proliferator-activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis. AU - Wettstein,Guillaume, AU - Luccarini,Jean-Michel, AU - Poekes,Laurence, AU - Faye,Patrick, AU - Kupkowski,Francine, AU - Adarbes,Vanessa, AU - Defrêne,Evelyne, AU - Estivalet,Céline, AU - Gawronski,Xavier, AU - Jantzen,Ingrid, AU - Philippot,Alain, AU - Tessier,Julien, AU - Tuyaa-Boustugue,Pascale, AU - Oakley,Fiona, AU - Mann,Derek A, AU - Leclercq,Isabelle, AU - Francque,Sven, AU - Konstantinova,Irena, AU - Broqua,Pierre, AU - Junien,Jean-Louis, Y1 - 2017/06/19/ PY - 2017/03/17/received PY - 2017/05/11/revised PY - 2017/05/19/accepted PY - 2018/2/7/entrez PY - 2018/2/7/pubmed PY - 2018/2/7/medline SP - 524 EP - 537 JF - Hepatology communications JO - Hepatol Commun VL - 1 IS - 6 N2 - 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). SN - 2471-254X UR - https://www.unboundmedicine.com/medline/citation/29404476/The_new_generation_pan_peroxisome_proliferator_activated_receptor_agonist_IVA337_protects_the_liver_from_metabolic_disorders_and_fibrosis_ L2 - https://doi.org/10.1002/hep4.1057 DB - PRIME DP - Unbound Medicine ER -
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