一种新型GLP-1和FGF21融合蛋白治疗非酒精性脂肪性肝炎(NASH)

IF 3.1 Q2 PHARMACOLOGY & PHARMACY
Advanced pharmaceutical bulletin Pub Date : 2024-12-10 eCollection Date: 2025-04-01 DOI:10.34172/apb.43672
Zhipeng Zhang, Yanqin Ma, Cheng Xie, Yan He, Dong Wang, Huaien Song, Miao Yuan, Xiaomei Zhang
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引用次数: 0

摘要

目的:本研究的目的是开发和生产一种结合GLP-1(胰高血糖素样肽-1)和FGF21(成纤维细胞生长因子21)的新型融合蛋白,目的是通过靶向双途径实现协同药理作用,随后在非酒精性脂肪性肝炎(NASH)模型中验证这些作用。方法:采用C57Bl/6J小鼠建立高脂饮食(HFD)/CCl4 NASH模型,评估低、中、高(0.3、1、3 mpk)剂量组的药物疗效,每周给药2次,连续28天。结果:HSP763-01动物药理学实验显示,大鼠体重明显减轻,但无明显食欲抑制。血液生化指标分析显示,甘油三酯(TG)、血清总胆固醇(TCHO或TC)、低密度脂蛋白(LDL)和血糖水平显著降低,并具有显著的剂量依赖效应。此外,肝组织分析显示肝脏脂肪变性和球囊变性明显减轻,小叶炎症部分缓解,具有显著的剂量依赖效应。然而,由于四氯甲烷(CCl4)在小鼠中引起严重的肝纤维化(3级),HSP763-01在缓解纤维化方面的作用有限。结论:HSP763-01具有明确的GLP-1和FGF21双重靶点,对HFD/CCl4模型有较强的反应,表现出明显的脂质代谢改善,血糖降低,体重减轻,肝脏脂肪变性,水肿明显减轻,小叶炎症和纤维化部分缓解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A Novel GLP-1 and FGF21 Fusion Protein for the Treatment of Non-alcoholic Steatohepatitis (NASH).

Purpose: The objective of this study was to develop and produce a novel fusion protein that combines GLP-1 (glucagon-like peptide-1) and FGF21 (fibroblast growth factor 21), with the aim of achieving synergistic pharmacological effects through the targeting of dual pathways, followed by validation of these effects in a non-alcoholic steatohepatitis (NASH) model.

Methods: We utilized C57Bl/6J mice to establish a high-fat diet (HFD)/CCl4 NASH model, with the aim of assessing the drug efficacy across low, medium, and high (0.3, 1, 3 mpk) dose groups administered twice a week for 28 days.

Results: The animal pharmacological experiment of HSP763-01 demonstrated a significant reduction in body weight without apparent appetite suppression. Analysis of blood biochemical indicators revealed a marked decrease in triglycerides (TG), serum total cholesterol (TCHO or TC), low-density lipoprotein (LDL), and blood sugar levels with a significant dose-dependent effect. Additionally, Liver tissue analysis indicated notable alleviation of liver fatty degeneration and ballooning degeneration, as well as partial relief of lobular inflammation with a significant dose-dependent effect. However, due to the severe liver fibrosis induced by tetrachloromethane (CCl4) in mice (3rd grade), HSP763-01 exhibited limited efficacy in alleviating fibrosis.

Conclusion: HSP763-01 exhibited a clear dual target of GLP-1 and FGF21, which has been demonstrated by a robust response to the HFD/CCl4 model, showing a marked improvement in lipid metabolism, lowering of blood glucose, weight loss, significant alleviation of liver steatosis, ballooning, and partial relief of lobular inflammation and fibrosis.

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来源期刊
Advanced pharmaceutical bulletin
Advanced pharmaceutical bulletin PHARMACOLOGY & PHARMACY-
CiteScore
6.80
自引率
2.80%
发文量
51
审稿时长
12 weeks
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