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
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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DOI：
10.1152/ajpgi.00157.2022
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发表时间：
2023-05-01
影响因子：
4.5
通讯作者：
Oro, Denise
中科院分区：
文献类型：
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作者：
Nielsen, Malte Hasle;Gillum, Matthew P.;Oro, Denise
成纤维细胞生长因子21(FGF21)在肝脏脂质代谢中起关键作用，长效FGF21类似物已成为治疗非酒精性脂肪性肝炎(NASH)的候选药物。这类药物的特征还有待于用翻译动物模型概括人类疾病的病因学和特征。为此，我们评估了长效成纤维细胞生长因子21类似物PF-05231023在GaN(Gubra Amylin Nash)饮食诱导的肥胖(DIO)和经活检证实的NASH小鼠模型中的作用。在研究开始之前，雄性C57BL/6J小鼠被喂以高脂肪、高果糖和高胆固醇的GaN饮食34wk。肝纤维化(F1期)的GaN DIO-NASH小鼠接受PF-05231023(10 mg/kg sc)或赋形剂(Sc)治疗12wk。以C57BL/6J小鼠为健康对照。肝活检前后进行组织病理学评分，对NAFLD活动性评分(NAS)和肝纤维化分期进行受试者内评估。终点包括定量肝组织学和转录组签名，以及血液和肝脏生化。PF-05231023显著降低了GaN-DIO-NASH小鼠的体重、肝脏肿大、血浆转氨酶和血浆/肝脂。值得注意的是，PF-05231023降低了NAS(改善2个点)和纤维化阶段(改善1个点)。脂肪变性、炎症和纤维化的定量组织学标志物的减少以及与疾病相关的肝脏转录组特征的改善支持了NASH和纤维化严重程度的改善。结论：PF-05231023可降低NASH小鼠模型中的NASH和纤维化严重程度，支持FGF21类似物治疗NASH的开发。因此，我们在翻译饮食诱导的肥胖和活检证实的NASH小鼠模型中描述了临床上相关的FGF21类似物PF-05231023。我们发现PF-05231023发挥了保护肝脏的作用，显著改善了血浆标志物和NASH的组织学特征，包括改善了纤维化阶段。总而言之，本研究支持继续开发长效的FGF21类似物来治疗NASH和其他纤维化疾病。
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 con-clusion, 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 explora-tion of long-acting FGF21 analogs for the treatment of NASH and other fibrotic diseases.