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

Autor: Duvivier V; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France., Creusot S; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France., Broux O; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France., Helbert A; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France., Lesage L; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France., Moreau K; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France., Lesueur N; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France., Gerard L; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France., Lemaitre K; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France., Provost N; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France., Hubert EL; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France., Baltauss T; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France., Brzustowski A; Centre de Recherche sur L'inflammation, Inserm, UMR, Paris, 1149, France., De Preville N; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France., Geronimi J; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France., Adoux L; GenomIC Université de Paris, Institut Cochin, INSERM, CNRS, Paris, F-75014, France., Letourneur F; GenomIC Université de Paris, Institut Cochin, INSERM, CNRS, Paris, F-75014, France., Hammoutene A; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France.; Pathology Department, Hôpital Beaujon, Paris, France., Valla D; 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., Paradis V; Pathology Department, Hôpital Beaujon, Paris, France., Delerive P; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France.
Jazyk: angličtina
Zdroj: Journal of clinical and experimental hepatology [J Clin Exp Hepatol] 2022 Mar-Apr; Vol. 12 (2), pp. 293-305. Date of Electronic Publication: 2021 Sep 08.
DOI: 10.1016/j.jceh.2021.09.001
Abstrakt: 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.
(© 2021 The Authors.)
Databáze: MEDLINE
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