Development of human growth hormone-treated chimeric mice with humanized livers for an evaluation model of drug-induced fatty liver disease.

IF 4.8 2区 医学 Q1 TOXICOLOGY
Sho Morioka, Seigo Sanoh, Yuji Ishida, Suzue Furukawa, Yuko Ogawa, Yaichiro Kotake, Chise Tateno
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Abstract

Chimeric mice with humanized livers were used to evaluate drug-induced liver injury (DILI). However, lipid accumulation is observed in the human hepatocytes of chimeric mice because of human growth hormone deficiency (GHD), which is an obstacle in the evaluation of drug-induced fatty liver disease (DIFLD), a common type of DILI. Previously, we showed that lipid droplets were reduced by the administration of human growth hormone (h-GH) to chimeric mice. Although h-GH administration reduces the lipid droplets, an optimal h-GH treatment method for assessing DIFLD has not yet been developed. This study investigated the appropriate h-GH dosage required to reduce lipid droplets and reproduce physiological conditions in humans. Moreover, the LXR agonist TO901317 was administered to h-GH-treated chimeric mice to evaluate the new h-GH treatment's effectiveness for DIFLD assessment. The results in blood h-GH levels, oil-red O liver sections, and gene expression levels in the liver suggested that 0.25 mg/kg/day would be an appropriate h-GH dosage to reduce lipid droplets and reproduce human physiological condition. At this dose, TO901317-induced lipid accumulation and lipid synthesis-related gene expression in humanized livers in a dose-dependent manner, suggesting that this new mouse model could be useful for evaluating human DIFLD. In summary, the administration of h-GH at an appropriate dosage regulated lipid homeostasis in the humanized livers of chimeric mice and h-GH-administered chimeric mice may represent a highly sensitive evaluation model for human DIFLD. The study also suggests a correlation between GH levels and lipid metabolism, potentially related to conditions like GHD and aging.

人生长激素处理的人源化肝脏嵌合小鼠的发展作为药物性脂肪肝疾病的评估模型。
采用人源化肝脏嵌合小鼠评价药物性肝损伤(DILI)。然而,由于人生长激素缺乏症(GHD),在嵌合小鼠的人肝细胞中观察到脂质积累,这是评估药物性脂肪性肝病(DIFLD)的障碍,DIFLD是DILI的一种常见类型。在此之前,我们发现嵌合小鼠使用人类生长激素(h-GH)可以减少脂滴。虽然h-GH可以减少脂滴,但目前尚未开发出评估DIFLD的最佳h-GH治疗方法。本研究探讨了人体减少脂滴和重现生理状况所需的适当h-GH剂量。此外,将LXR激动剂TO901317给予h-GH处理的嵌合小鼠,以评估新的h-GH治疗对DIFLD的有效性。血h-GH水平、油红O型肝切片和肝脏基因表达水平表明,0.25 mg/kg/天的h-GH剂量可以减少脂滴,重现人体生理状态。在此剂量下,to901317诱导人源肝脏中脂质积累和脂质合成相关基因表达呈剂量依赖性,表明该小鼠模型可用于评估人DIFLD。综上所述,适当剂量的h-GH可以调节嵌合小鼠人源化肝脏中的脂质稳态,而h-GH给药的嵌合小鼠可能是一种高度敏感的人DIFLD评估模型。该研究还表明生长激素水平与脂质代谢之间存在相关性,这可能与GHD和衰老等疾病有关。
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来源期刊
Archives of Toxicology
Archives of Toxicology 医学-毒理学
CiteScore
11.60
自引率
4.90%
发文量
218
审稿时长
1.5 months
期刊介绍: Archives of Toxicology provides up-to-date information on the latest advances in toxicology. The journal places particular emphasis on studies relating to defined effects of chemicals and mechanisms of toxicity, including toxic activities at the molecular level, in humans and experimental animals. Coverage includes new insights into analysis and toxicokinetics and into forensic toxicology. Review articles of general interest to toxicologists are an additional important feature of the journal.
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