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单剂和多剂塞拉德尔帕降低了小鼠胆汁酸合成的日常标记物

Edward E Cable¹, Jeffrey W Stebbins¹, Jeff D Johnson¹

¹CymaBay Therapeutics Inc., Fremont, California, USA.

|April 14, 2025

概括

塞拉德尔帕是一种PPARδ激动剂,通过增加FGF21和改变小鼠的基因表达,减少胆酸合成. 这种PPAR激动剂显示了胆固醇疾病的治疗潜力.

科学领域:

药理学药理学是指药理学的学科.
肝病学肝病学是一种肝病学.
分子生物学分子生物学

背景情况:

过氧体增殖器激活受体 (PPARs) 是胆酸代谢的关键调节者.
PPAR激动剂是胆固醇性肝脏疾病的潜在治疗方法.
了解seladelpar对胆酸生物合成和基因表达的影响至关重要.

研究的目的:

为了研究单剂和多剂PPARδ激动剂seladelpar对小鼠胆酸代谢和基因表达的影响.
评估塞拉德帕对血C4 (胆酸生物合成代理) 和纤维细胞生长因子21 (Fgf21) 水平的影响.
为了分析seladelpar治疗引起的肝脏基因表达变化.

主要方法:

雄性和雌性C57BL/6小鼠通过口腔 gavage 给予seladelpar (10 mg/kg/day) 或载体.
血C4和Fgf21水平在剂后的不同时间点被测量.
使用非向RNA测序分析肝脏基因表达.

主要成果:

在雄性和雌性小鼠中,塞拉德尔帕显著降低了血C4和增加了血Fgf21水平.
治疗降低了胆固醇7α-基酶mRNA和增加了Fgf21mRNA在肝脏.
RNA测序揭示了PPAR响应基因的上调和单剂量和多剂量效应之间的强烈相关性.

结论:

塞拉德尔帕治疗有效地减少了小鼠的胆酸合成.
该机制涉及Fgf21的上调和对其他PPAR响应基因的调节.
这些发现支持seladelpar作为治疗胆固醇疾病的治疗剂的潜力.

关键词:

这是一个PPAR.这是一个PPAR delta.胆汁代谢胆汁代谢昼夜节律昼夜节律塞拉德帕尔 (塞拉德帕尔) 是一个位于西兰的公园.

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