François Briand1, Julie Maupoint2, Emmanuel Brousseau3, Natalia Breyner3, Mélanie Bouchet3, Clément Costard2, Thierry Leste-Lasserre4, Mathieu Petitjean5, Li Chen5, Audrey Chabrat6, Virgile Richard6, Rémy Burcelin7, Caroline Dubroca2, Thierry Sulpice8. 1. Physiogenex, 280 rue de l'Hers, ZAC de la Masquère, 31750 Escalquens, France. Electronic address: f.briand@physiogenex.com. 2. Cardiomedex, 280 rue de l'Hers, ZAC de la Masquère, 31750 Escalquens, France. 3. Physiogenex, 280 rue de l'Hers, ZAC de la Masquère, 31750 Escalquens, France. 4. Neurocentre Magendie, 146 rue Léo Saignat, 33077 Bordeaux cedex, France. 5. PharmaNest, 100 Overlook Center, FL2, Princeton, NJ 08540, United States of America. 6. Sciempath Labo, 7 rue de la Gratiole, 37270 Larcay, France. 7. Inserm U1048 CHU Rangueil, BP 84225, 31432 Toulouse Cedex 4, France. 8. Physiogenex, 280 rue de l'Hers, ZAC de la Masquère, 31750 Escalquens, France; Cardiomedex, 280 rue de l'Hers, ZAC de la Masquère, 31750 Escalquens, France.
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.
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: Victoria Svop Jensen; Christian Fledelius; Erik Max Wulff; Jens Lykkesfeldt; Henning Hvid Journal: Nutrients Date: 2021-02-12 Impact factor: 5.717