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.
Highlights
Non-alcoholic steatohepatitis (NASH) is the most rapidly growing liver disease that is without approved pharmacological treatment
For the experiment 20–22 week old male APOE*3Leiden.cholesteryl ester transfer protein (CETP) mice were matched on age, body weight, blood glucose and plasma cholesterol and triglycerides into one age-matched healthy reference group of 8 mice that were kept on the healthy chow diet (R/M-H, Ssniff Spezialdieten GmbH, Soest, Germany) and a group of 36 mice that were given a high fat and cholesterol diet (HFC) containing 45 kcal% fat derived from lard (Cat. no. 12451), supplemented with 1% (w/w) cholesterol (Research Diets, New Brunswick, NJ, USA) for 15 weeks to induce NASH
The HFC diet resulted in a gradual increase in perigonadal, visceral and subcutaneous white adipose tissue (WAT) weights after 15 weeks (HFC reference group) and 25 weeks (HFC control group), while treatment with elafibranor resulted in significantly lower WAT weights as compared to the HFC control group
Summary
Non-alcoholic steatohepatitis (NASH) is the most rapidly growing liver disease that is without approved pharmacological treatment. 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. The model has been proven to respond to several hypolipidemic and anti-diabetic drugs as in h umans[20,21,22,23,24,25,26,27] Using this translational model, we evaluated the response of elafibranor on plasma parameters and NASH histopathology, and hepatic transcriptome analysis was used to investigate the underlying pathways affected by elafibranor. The underlying disease pathways of the model were compared with those of NASH patients and we discuss the response of elafibranor in the mice as compared to the response in human patients, as well as potential pitfalls when translating preclinical results of novel NASH therapeutics to human patients
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