Characterization and Pharmacological Validation of a Preclinical Model of NASH in Göttingen Minipigs

Valérie Duvivier; Stéphanie Creusot; Olivier Broux; Aurélie Helbert; Ludovic Lesage; Kevin Moreau; Nicolas Lesueur; Lindsay Gerard; Karine Lemaitre; Nicolas Provost; Edwige-Ludiwyne Hubert; Tania Baltauss; Angelique Brzustowski; Nathalie De Preville; Julia Geronimi; Lucie Adoux; Franck Letourneur; Adel Hammoutene; Dominique Valla; Valérie Paradis; Philippe Delerive

doi:10.1016/j.jceh.2021.09.001

Characterization and Pharmacological Validation of a Preclinical Model of NASH in Göttingen Minipigs

J Clin Exp Hepatol. 2022 Mar-Apr;12(2):293-305. doi: 10.1016/j.jceh.2021.09.001. Epub 2021 Sep 8.

Authors

Valérie Duvivier¹, Stéphanie Creusot¹, Olivier Broux¹, Aurélie Helbert¹, Ludovic Lesage¹, Kevin Moreau¹, Nicolas Lesueur¹, Lindsay Gerard¹, Karine Lemaitre¹, Nicolas Provost¹, Edwige-Ludiwyne Hubert¹, Tania Baltauss¹, Angelique Brzustowski², Nathalie De Preville¹, Julia Geronimi¹, Lucie Adoux³, Franck Letourneur³, Adel Hammoutene^{1

4}, Dominique Valla⁵, Valérie Paradis⁴, Philippe Delerive¹

Affiliations

¹ Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France.
² Centre de Recherche sur L'inflammation, Inserm, UMR, Paris, 1149, France.
³ GenomIC Université de Paris, Institut Cochin, INSERM, CNRS, Paris, F-75014, France.
⁴ Pathology Department, Hôpital Beaujon, Paris, France.
⁵ Université de Paris, AP-HP, Hôpital Beaujon, Service D'Hépatologie, DMU DIGEST, Centre de Référence des Maladies Vasculaires Du Foie, FILFOIE, ERN RARE-LIVER, Centre de Recherche sur L'inflammation, Inserm, UMR, Paris, 1149, France.

Abstract

Background: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, which is associated with features of metabolic syndrome. NAFLD may progress in a subset of patients into nonalcoholic steatohepatitis (NASH) with liver injury resulting ultimately in cirrhosis and potentially hepatocellular carcinoma. Today, there is no approved treatment for NASH due to, at least in part, the lack of preclinical models recapitulating features of human disease. Here, we report the development of a dietary model of NASH in the Göttingen minipig.

Methods: First, we performed a longitudinal characterization of diet-induced NASH and fibrosis using biochemical, histological, and transcriptional analyses. We then evaluated the pharmacological response to Obeticholic acid (OCA) treatment for 8 weeks at 2.5mg/kg/d, a dose matching its active clinical exposure.

Results: Serial histological examinations revealed a rapid installation of NASH driven by massive steatosis and inflammation, including evidence of ballooning. Furthermore, we found the progressive development of both perisinusoidal and portal fibrosis reaching fibrotic septa after 6 months of diet. Histological changes were mechanistically supported by well-defined gene signatures identified by RNA Seq analysis. While treatment with OCA was well tolerated throughout the study, it did not improve liver dysfunction nor NASH progression. By contrast, OCA treatment resulted in a significant reduction in diet-induced fibrosis in this model.

Conclusions: These results, taken together, indicate that the diet-induced NASH in the Göttingen minipig recapitulates most of the features of human NASH and may be a model with improved translational value to prioritize drug candidates toward clinical development.

Keywords: CDAHFD, choline-deficient amino acid-defined high fat diet; FDR, false discovery rate; FFC, fatfructose cholesterol diet; NAFLD, nonalcoholic fatty liver disease; NAS, NAFLD activity score; NASH; NASH, nonalcoholic steatohepatitis; PNPLA3, patatin-like phospholipase domain-containing 3; minipig; translational value.