Hepatoprotective effects of the long-acting fibroblast growth factor 21 analog PF-05231023 in the GAN diet-induced obese and biopsy-confirmed mouse model of nonalcoholic steatohepatitis
| العنوان: | Hepatoprotective effects of the long-acting fibroblast growth factor 21 analog PF-05231023 in the GAN diet-induced obese and biopsy-confirmed mouse model of nonalcoholic steatohepatitis |
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| المؤلفون: | Malte Hasle Nielsen, Matthew P. Gillum, Niels Vrang, Jacob Jelsing, Henrik H. Hansen, Michael Feigh, Denise Oró |
| المصدر: | Nielsen, M H, Gillum, M P, Vrang, N, Jelsing, J, Hansen, H H, Feigh, M & Oró, D 2023, ' Hepatoprotective effects of the long-acting fibroblast growth factor 21 analog PF-05231023 in the GAN diet-induced obese and biopsy-confirmed mouse model of nonalcoholic steatohepatitis ', American Journal of Physiology: Gastrointestinal and Liver Physiology, vol. 324, no. 5, pp. G378-G388 . https://doi.org/10.1152/ajpgi.00157.2022 |
| بيانات النشر: | American Physiological Society, 2023. |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | Male, Liver/metabolism, Hepatology, Physiology, Biopsy, Gastroenterology, Liver Cirrhosis/metabolism, Diet, Mice, Inbred C57BL, Mice, Disease Models, Animal, Non-alcoholic Fatty Liver Disease/drug therapy, Physiology (medical), Obesity/metabolism, Diet, High-Fat/adverse effects, Animals, Humans |
| الوصف: | Fibroblast growth factor 21 (FGF21) plays a key role in hepatic lipid metabolism and long-acting FGF21 analogs have emerged aspromising drug candidates for the treatment of nonalcoholic steatohepatitis (NASH). It remains to characterize this drug class intranslational animal models that recapitulate the etiology and hallmarks of human disease. To this end, we evaluated the longactingFGF21 analog PF-05231023 in the GAN (Gubra Amylin NASH) diet-induced obese (DIO) and biopsy-confirmed mousemodel of NASH. Male C57BL/6J mice were fed the GAN diet high in fat, fructose, and cholesterol for 34 wk before the start ofthe study. GAN DIO-NASH mice with biopsy-confirmed NAFLD Activity Score (NAS 5) and fibrosis (stage F1) were biweeklyadministered with PF-05231023 (10 mg/kg sc) or vehicle (sc) for 12 wk. Vehicle-dosed chow-fed C57BL/6J mice served ashealthy controls. Pre-to-post liver biopsy histopathological scoring was performed for within-subject evaluation of NAFLD ActivityScore (NAS) and fibrosis stage. Terminal endpoints included quantitative liver histology and transcriptome signatures as well asblood and liver biochemistry. PF-05231023 significantly reduced body weight, hepatomegaly, plasma transaminases, andplasma/liver lipids in GAN DIO-NASH mice. Notably, PF-05231023 reduced both NAS (2-point improvement) and fibrosis stage(1-point improvement). Improvements in NASH and fibrosis severity were supported by reduced quantitative histological markersof steatosis, inflammation, and fibrogenesis as well as improvements in disease-associated liver transcriptome signatures. In conclusion,PF-05231023 reduces NASH and fibrosis severity in a translational biopsy-confirmed mouse model of NASH, supportingdevelopment of FGF21 analogs for the treatment of NASH.NEW & NOTEWORTHY It is unclear if long-acting FGF21 analogs have antifibrotic efficacy in NASH. We therefore profiled theclinically relevant FGF21 analog PF-05231023 in a translational diet-induced obese and biopsy-confirmed mouse model ofNASH. We found PF-05231023 to exert hepatoprotective effects as indicated by notable improvements in plasma markers andhistological hallmarks of NASH, including improved fibrosis stage. Collectively, the present study supports the continued explorationof long-acting FGF21 analogs for the treatment of NASH and other fibrotic diseases. Fibroblast growth factor 21 (FGF21) plays a key role in hepatic lipid metabolism and long-acting FGF21 analogs have emerged as promising drug candidates for the treatment of nonalcoholic steatohepatitis (NASH). It remains to characterize this drug class in translational animal models that recapitulate the etiology and hallmarks of human disease. To this end, we evaluated the long-acting FGF21 analog PF-05231023 in the GAN (Gubra Amylin NASH) diet-induced obese (DIO) and biopsy-confirmed mouse model of NASH. Male C57BL/6J mice were fed the GAN diet high in fat, fructose, and cholesterol for 34 wk before the start of the study. GAN DIO-NASH mice with biopsy-confirmed NAFLD Activity Score (NAS ≥5) and fibrosis (stage ≥F1) were biweekly administered with PF-05231023 (10 mg/kg sc) or vehicle (sc) for 12 wk. Vehicle-dosed chow-fed C57BL/6J mice served as healthy controls. Pre-to-post liver biopsy histopathological scoring was performed for within-subject evaluation of NAFLD Activity Score (NAS) and fibrosis stage. Terminal endpoints included quantitative liver histology and transcriptome signatures as well as blood and liver biochemistry. PF-05231023 significantly reduced body weight, hepatomegaly, plasma transaminases, and plasma/liver lipids in GAN DIO-NASH mice. Notably, PF-05231023 reduced both NAS (≥2-point improvement) and fibrosis stage (1-point improvement). Improvements in NASH and fibrosis severity were supported by reduced quantitative histological markers of steatosis, inflammation, and fibrogenesis as well as improvements in disease-associated liver transcriptome signatures. In conclusion, PF-05231023 reduces NASH and fibrosis severity in a translational biopsy-confirmed mouse model of NASH, supporting development of FGF21 analogs for the treatment of NASH.NEW & NOTEWORTHY It is unclear if long-acting FGF21 analogs have antifibrotic efficacy in NASH. We therefore profiled the clinically relevant FGF21 analog PF-05231023 in a translational diet-induced obese and biopsy-confirmed mouse model of NASH. We found PF-05231023 to exert hepatoprotective effects as indicated by notable improvements in plasma markers and histological hallmarks of NASH, including improved fibrosis stage. Collectively, the present study supports the continued exploration of long-acting FGF21 analogs for the treatment of NASH and other fibrotic diseases. |
| وصف الملف: | application/pdf |
| تدمد: | 1522-1547 0193-1857 |
| DOI: | 10.1152/ajpgi.00157.2022 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::60b52c708705dfac2ae90999b5b369cf https://doi.org/10.1152/ajpgi.00157.2022 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....60b52c708705dfac2ae90999b5b369cf |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15221547 01931857 |
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| DOI: | 10.1152/ajpgi.00157.2022 |