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.
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.
Authors: Paul Angulo; David E Kleiner; Sanne Dam-Larsen; Leon A Adams; Einar S Bjornsson; Phunchai Charatcharoenwitthaya; Peter R Mills; Jill C Keach; Heather D Lafferty; Alisha Stahler; Svanhildur Haflidadottir; Flemming Bendtsen Journal: Gastroenterology Date: 2015-04-29 Impact factor: 22.682
Authors: Y-L Liu; G L Patman; J B S Leathart; A-C Piguet; A D Burt; J-F Dufour; C P Day; A K Daly; H L Reeves; Q M Anstee Journal: J Hepatol Date: 2014-03-06 Impact factor: 25.083
Authors: Yi Luo; Samir Wadhawan; Alex Greenfield; Benjamin E Decato; Abdul M Oseini; Rebecca Collen; Diane E Shevell; John Thompson; Gabor Jarai; Edgar D Charles; Arun J Sanyal Journal: Hepatol Commun Date: 2021-01-20
Authors: Tiebing Liang; Mouhamad Alloosh; Lauren N Bell; Allison Fullenkamp; Romil Saxena; William Van Alstine; Phelan Bybee; Klára Werling; Michael Sturek; Naga Chalasani; Howard C Masuoka Journal: PLoS One Date: 2015-05-15 Impact factor: 3.240
Authors: Jonathan D Roth; Michael Feigh; Sanne S Veidal; Louise Kd Fensholdt; Kristoffer T Rigbolt; Henrik H Hansen; Li C Chen; Mathieu Petitjean; Weslyn Friley; Niels Vrang; Jacob Jelsing; Mark Young Journal: World J Gastroenterol Date: 2018-01-14 Impact factor: 5.742