Beneficial effects of elafibranor on NASH in E3L.CETP mice and differences between mice and men

Abstract Non-alcoholic steatohepatitis (NASH) is the most rapidly growing liver disease that is nevertheless without approved pharmacological treatment. Despite great effort in developing novel NASH therapeutics, many have failed in clinical trials. This has raised questions on the adequacy of precl...

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Autores principales:	Anita M. van den Hoek, Lars Verschuren, Martien P. M. Caspers, Nicole Worms, Aswin L. Menke, Hans M. G. Princen
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b01d71c202e84e7d903bdef458f54ea0
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spelling	oai:doaj.org-article:b01d71c202e84e7d903bdef458f54ea02021-12-02T11:37:22ZBeneficial effects of elafibranor on NASH in E3L.CETP mice and differences between mice and men10.1038/s41598-021-83974-82045-2322https://doaj.org/article/b01d71c202e84e7d903bdef458f54ea02021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83974-8https://doaj.org/toc/2045-2322Abstract Non-alcoholic steatohepatitis (NASH) is the most rapidly growing liver disease that is nevertheless without approved pharmacological treatment. Despite great effort in developing novel NASH therapeutics, many have failed in clinical trials. This has raised questions on the adequacy of preclinical models. Elafibranor is one of the drugs currently in late stage development which had mixed results for phase 2/interim phase 3 trials. In the current study we investigated the response of elafibranor in APOE*3Leiden.CETP mice, a translational animal model that displays histopathological characteristics of NASH in the context of obesity, insulin resistance and hyperlipidemia. To induce NASH, mice were fed a high fat and cholesterol (HFC) diet for 15 weeks (HFC reference group) or 25 weeks (HFC control group) or the HFC diet supplemented with elafibranor (15 mg/kg/d) from week 15–25 (elafibranor group). The effects on plasma parameters and NASH histopathology were assessed and hepatic transcriptome analysis was used to investigate the underlying pathways affected by elafibranor. Elafibranor treatment significantly reduced steatosis and hepatic inflammation and precluded the progression of fibrosis. The underlying disease pathways of the model were compared with those of NASH patients and illustrated substantial similarity with molecular pathways involved, with 87% recapitulation of human pathways in mice. We compared the response of elafibranor in the mice to the response in human patients and discuss potential pitfalls when translating preclinical results of novel NASH therapeutics to human patients. When taking into account that due to species differences the response to some targets, like PPAR-α, may be overrepresented in animal models, we conclude that elafibranor may be particularly useful to reduce hepatic inflammation and could be a pharmacologically useful agent for human NASH, but probably in combination with other agents.Anita M. van den HoekLars VerschurenMartien P. M. CaspersNicole WormsAswin L. MenkeHans M. G. PrincenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anita M. van den Hoek Lars Verschuren Martien P. M. Caspers Nicole Worms Aswin L. Menke Hans M. G. Princen Beneficial effects of elafibranor on NASH in E3L.CETP mice and differences between mice and men
description	Abstract Non-alcoholic steatohepatitis (NASH) is the most rapidly growing liver disease that is nevertheless without approved pharmacological treatment. Despite great effort in developing novel NASH therapeutics, many have failed in clinical trials. This has raised questions on the adequacy of preclinical models. Elafibranor is one of the drugs currently in late stage development which had mixed results for phase 2/interim phase 3 trials. In the current study we investigated the response of elafibranor in APOE*3Leiden.CETP mice, a translational animal model that displays histopathological characteristics of NASH in the context of obesity, insulin resistance and hyperlipidemia. To induce NASH, mice were fed a high fat and cholesterol (HFC) diet for 15 weeks (HFC reference group) or 25 weeks (HFC control group) or the HFC diet supplemented with elafibranor (15 mg/kg/d) from week 15–25 (elafibranor group). The effects on plasma parameters and NASH histopathology were assessed and hepatic transcriptome analysis was used to investigate the underlying pathways affected by elafibranor. Elafibranor treatment significantly reduced steatosis and hepatic inflammation and precluded the progression of fibrosis. The underlying disease pathways of the model were compared with those of NASH patients and illustrated substantial similarity with molecular pathways involved, with 87% recapitulation of human pathways in mice. We compared the response of elafibranor in the mice to the response in human patients and discuss potential pitfalls when translating preclinical results of novel NASH therapeutics to human patients. When taking into account that due to species differences the response to some targets, like PPAR-α, may be overrepresented in animal models, we conclude that elafibranor may be particularly useful to reduce hepatic inflammation and could be a pharmacologically useful agent for human NASH, but probably in combination with other agents.
format	article
author	Anita M. van den Hoek Lars Verschuren Martien P. M. Caspers Nicole Worms Aswin L. Menke Hans M. G. Princen
author_facet	Anita M. van den Hoek Lars Verschuren Martien P. M. Caspers Nicole Worms Aswin L. Menke Hans M. G. Princen
author_sort	Anita M. van den Hoek
title	Beneficial effects of elafibranor on NASH in E3L.CETP mice and differences between mice and men
title_short	Beneficial effects of elafibranor on NASH in E3L.CETP mice and differences between mice and men
title_full	Beneficial effects of elafibranor on NASH in E3L.CETP mice and differences between mice and men
title_fullStr	Beneficial effects of elafibranor on NASH in E3L.CETP mice and differences between mice and men
title_full_unstemmed	Beneficial effects of elafibranor on NASH in E3L.CETP mice and differences between mice and men
title_sort	beneficial effects of elafibranor on nash in e3l.cetp mice and differences between mice and men
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/b01d71c202e84e7d903bdef458f54ea0
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Beneficial effects of elafibranor on NASH in E3L.CETP mice and differences between mice and men

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