Elafibranor improves diet-induced nonalcoholic steatohepatitis associated with heart failure with preserved ejection fraction in Golden Syrian hamsters.

Abstract

BACKGROUND:

Cardiovascular disease is the leading cause of deaths in nonalcoholic steatohepatitis (NASH) patients. Mouse models, while widely used for drug development, do not fully replicate human NASH nor integrate the associated cardiac dysfunction, i.e. heart failure with preserved ejection fraction (HFpEF). To overcome these limitations, we established a nutritional hamster model developing both NASH and HFpEF. We then evaluated the effects of the dual peroxisome proliferator activated receptor alpha/delta agonist elafibranor developed for the treatment of NASH patients.

METHODS:

Male Golden Syrian hamsters were fed for 10 to 20 weeks with a free choice diet, which presents hamsters with a choice between control chow diet with normal drinking water or a high fat/high cholesterol diet with 10% fructose enriched drinking water. Biochemistry, histology and echocardiography analysis were performed to characterize NASH and HFpEF. Once the model was validated, elafibranor was evaluated at 15 mg/kg/day orally QD for 5 weeks.

RESULTS:

Hamsters fed a free choice diet for up to 20 weeks developed NASH, including hepatocyte ballooning (as confirmed with cytokeratin-18 immunostaining), bridging fibrosis, and a severe diastolic dysfunction with restrictive profile, but preserved ejection fraction. Elafibranor resolved NASH, with significant reduction in ballooning and fibrosis scores, and improved diastolic dysfunction with significant reduction in E/A and E/E' ratios.

CONCLUSION:

Our data demonstrate that the free choice diet induced NASH hamster model replicates the human phenotype and will be useful for validating novel drug candidates for the treatment of NASH and associated HFpEF.

• Authors: François Briand, Julie Maupoint, Emmanuel Brousseau, Natalia Breyner, Mélanie Bouchet, Clément Costard, Thierry Leste-Lasserre, Mathieu Petitjean, Li Chen, Audrey Chabrat, Virgile Richard, Rémy Burcelin, Caroline Dubroca, Thierry Sulpice
• Journal: Metabolism: clinical and experimental (Metabolism) Vol. 117 Pg. 154707 (04 2021) ISSN: 1532-8600 [Electronic] United States
• PMID: 33444606 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• 2-(2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxo-1-propenyl)phenoxyl)-2-methylpropanoic acid
• Chalcones
• PPAR alpha
• PPAR delta
• Propionates
• Fructose
• Cholesterol

Topics

• Animals
• Chalcones (pharmacology)
• Cholesterol (metabolism)
• Diet, High-Fat (adverse effects)
• Disease Models, Animal
• Fructose (metabolism)
• Heart Failure (drug therapy, metabolism)
• Hepatocytes (drug effects, metabolism)
• Liver (drug effects, metabolism)
• Liver Cirrhosis (drug therapy, metabolism)
• Male
• Mesocricetus
• Non-alcoholic Fatty Liver Disease (drug therapy, metabolism)
• PPAR alpha (metabolism)
• PPAR delta (metabolism)
• Propionates (pharmacology)