Single and Multiple Doses of Seladelpar Decrease Diurnal Markers of Bile Acid Synthesis in Mice.

IF 3.5 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
PPAR Research Pub Date : 2025-03-11 eCollection Date: 2025-01-01 DOI:10.1155/ppar/5423221
Edward E Cable, Jeffrey W Stebbins, Jeff D Johnson, Yun-Jung Choi, Jiangao Song, Sole Gatto, Matthew Onorato, Charles A McWherter
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引用次数: 0

Abstract

Peroxisome proliferator-activated receptors (PPARs) modulate bile metabolism and are important therapeutic options in cholestatic diseases. This study was aimed at understanding the effects of single and multiple doses of seladelpar, a PPARδ (peroxisome proliferator-activated receptor delta) agonist, on plasma C4 (a freely diffusible metabolite accepted as a proxy for de novo bile acid biosynthesis), Fibroblast Growth Factor 21 (Fgf21), and gene expression changes in the liver of male and female mice. C57BL/6 mice were treated with seladelpar 10 mg/kg/day or vehicle through oral gavage before lights out on Day 1 (single dose) or from Day 1 to Day 7 (multiple doses). Liver samples were obtained at 0, 1, 2, 4, 8, 12, 16, and 24 h postdosing, and plasma C4 and Fgf21 levels were measured. In vehicle-treated mice, C4 levels were higher in the dark cycle compared to the light cycle, with higher levels in females than in males. Plasma Fgf21 did not vary substantially over the dark-light cycle or show a sex-specific expression pattern. Seladelpar treatment significantly reduced plasma C4 and increased Fgf21 levels in both sexes, which coincided with a decrease in cholesterol 7α-hydroxylase mRNA and an increase in Fgf21 mRNA in the livers. Untargeted RNA sequencing revealed a strong correlation between the genes differentially expressed after single- and multiple-dose seladelpar treatment. PPAR-responsive genes, including pyruvate dehydrogenase kinase 4, acyl-CoA thioesterase 2, and angiopoietin-like 4, were upregulated. No changes in nuclear receptors, clock genes, and sex-specific genes were observed. Overall, these results are consistent with a model where seladelpar treatment reduces bile acid synthesis by upregulating Fgf21 and modulating other PPAR-responsive genes.

单剂量和多剂量Seladelpar降低小鼠胆汁酸合成的日标记物。
过氧化物酶体增殖物激活受体(PPARs)调节胆汁代谢,是胆汁淤积性疾病的重要治疗选择。本研究旨在了解单剂量和多剂量seladelpar(一种PPARδ(过氧化物酶体增殖物激活受体)激动剂)对血浆C4(一种可自由扩散的代谢物,可作为新生胆汁酸生物合成的代谢物)、成纤维细胞生长因子21 (Fgf21)和雄性和雌性小鼠肝脏基因表达变化的影响。C57BL/6小鼠在第1天熄灯前口服10 mg/kg/天或对照药给药(单剂量)或第1 ~ 7天(多剂量)。在给药后0、1、2、4、8、12、16和24小时取肝脏样本,测定血浆C4和Fgf21水平。在给药小鼠中,C4水平在黑暗周期高于光照周期,雌性高于雄性。血浆Fgf21在暗光周期内没有显著变化,也没有表现出性别特异性的表达模式。Seladelpar治疗显著降低了两性血浆C4,增加了Fgf21水平,这与肝脏中胆固醇7α-羟化酶mRNA的降低和Fgf21 mRNA的增加相一致。非靶向RNA测序显示,单剂量和多剂量塞拉德帕治疗后基因差异表达之间存在很强的相关性。ppar应答基因,包括丙酮酸脱氢酶激酶4、酰基辅酶a硫酯酶2和血管生成素样4,均上调。核受体、时钟基因和性别特异性基因未见变化。总的来说,这些结果与seladelpar治疗通过上调Fgf21和调节其他ppar应答基因来减少胆汁酸合成的模型是一致的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
PPAR Research
PPAR Research MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
6.20
自引率
3.40%
发文量
17
审稿时长
12 months
期刊介绍: PPAR Research is a peer-reviewed, Open Access journal that publishes original research and review articles on advances in basic research focusing on mechanisms involved in the activation of peroxisome proliferator-activated receptors (PPARs), as well as their role in the regulation of cellular differentiation, development, energy homeostasis and metabolic function. The journal also welcomes preclinical and clinical trials of drugs that can modulate PPAR activity, with a view to treating chronic diseases and disorders such as dyslipidemia, diabetes, adipocyte differentiation, inflammation, cancer, lung diseases, neurodegenerative disorders, and obesity.
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