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.

Pemafibrate suppresses NLRP3 inflammasome activation in the liver and heart in a novel mouse model of steatohepatitis-related cardiomyopathy

“…Recent clinical studies have demonstrated that NAFLD is closely associated with cardiac dysfunction or atrial fibrillation 7 , 8 , 26 . Larger rodent animals, such as hamsters and rats, with steatohepatitis accompanied by cardiomyopathy have been reported 27 , 28 ; however, there is no report regarding a mouse model. In the current study, we developed a high fat/high cholesterol/high sucrose/bile acid diet 29 .…”

Alteration of the gut microbiota’s composition and metabolic output correlates with COVID-19-like severity in obese NASH hamsters

“…Liver histology (H&E and Sirius Red staining), NAFLD activity scoring and % Sirius Red labeling were performed as described previously. 62 Lung tissues were fixed in 4% PBS buffered formaldehyde for 7 days, rinsed in PBS, transferred in ethanol (70%) and then processed into paraffin-embedded tissues blocks. The subcontractor Sciempath Labo (Larçay, France) performed histological processing and analysis.…”

“…Final extraction and Mass spectrometry analysis were performed as already described. 62 SCFAs : sample preparation was adapted from protocol of Zheng and collaborators. 63 Approximatively 30 mg of fecal samples were used and suspended with 1050 µl of a solution of NaOH at 0.005 M including internal standard mix of acetate-D3, butyrate-13C2 and valerate-D9 at 61 µM and ceramic beads.…”

Metabolic Spectrum of Liver Failure in Type 2 Diabetes and Obesity: From NAFLD to NASH to HCC

“…It reduced histopathologically hepatic steatosis and inflammation, and reduced fibrosis severity in both NAFLD/NASH and fibrosis mouse models [ 146 , 147 ]. It tends to reduce body weight, but not liver weight in diet-induced NAFLD/NASH rodent models [ 148 , 149 ]. In obese patients, it improves hepatic and peripheral insulin sensitivity [ 150 ].…”