Effects of a novel selective PPARα modulator, statin, sodium-glucose cotransporter 2 inhibitor, and combinatorial therapy on the liver and vasculature of medaka nonalcoholic steatohepatitis model
Effects of a novel selective PPARα modulator, statin, sodium-glucose cotransporter 2 inhibitor, and combinatorial therapy on the liver and vasculature of medaka nonalcoholic steatohepatitis model
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新型选择性 PPARα 调节剂、他汀类药物、钠-葡萄糖协同转运蛋白 2 抑制剂及联合治疗对青鳉非酒精性脂肪性肝炎模型肝脏和血管的影响
DOI：
10.1016/j.bbrc.2022.01.086
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发表时间：
2022
影响因子：
3.1
通讯作者：
Terai Shuji
中科院分区：
文献类型：
--
作者：
Kimura Atsushi;Kamimura Kenya;Ohkoshi-Yamada Marina;Shinagawa-Kobayashi Yoko;Goto Ryo;Owaki Takashi;Oda Chiyumi;Shibata Osamu;Morita Shinichi;Sakai Norihiro;Abe Hiroyuki;Yokoo Takeshi;Sakamaki Akira;Kamimura Hiroteru;Terai Shuji
非酒精性脂肪性肝炎（NASH）是一种发病率不断增加的疾病，涉及多种代谢途径。各种器官，包括肝脏、肾脏和血管系统，在NASH中受损，这表明迫切需要开发标准治疗。因此，本研究进行了调查的药物靶向各种代谢途径和它们的组合对高脂饮食（HFD）诱导的NASH青鳉model.MethodsTo调查药物对血管结构的影响，NASH动物模型的开发使用thefli：：GFP转基因青鳉喂以20毫克/鱼每天。以时间依赖的方式评价了选择性过氧化物酶体增殖物激活受体α调节剂（培马贝特）、他汀类药物（匹伐他汀）、钠-葡萄糖协同转运蛋白2抑制剂（托佛格列汀）及其组合治疗后的生理变化、肝脏组织学变化、鳍血管结构和血清生化标志物。此外，以确定潜在的影响机制，全转录组测序进行青鳉肝脏samples.ResultsHistological分析显示显着抑制脂肪积累和肝纤维化的变化后，治疗药物及其组合。脂肪变性和纤维化相关基因的表达水平通过治疗改变。此外，HFD诱导的血管损伤的鳍表现出温和的变化后，治疗药物.ConclusionThe治疗各种代谢途径对青鳉体，肝脏和血管结构的NASH青鳉模型的影响被证明。此外，据我们所知，本研究首次报道了青鳉肝脏的全基因组序列和基因表达评估，这可能有助于阐明药物的分子机制。
ObjectiveNonalcoholic steatohepatitis (NASH) is a disease entity with an increasing incidence, with involvement of several metabolic pathways. Various organs, including the liver, kidneys, and the vasculature, are damaged in NASH, indicating the urgent need to develop a standard therapy. Therefore, this study was conducted to investigate the effects of drugs targeting various metabolic pathways and their combinations on a high-fat diet (HFD)-induced NASH medaka model.MethodsTo investigate the effects of drugs on vascular structures, the NASH animal model was developed using thefli::GFPtransgenic medaka fed with HFD at 20 mg/fish daily. The physiological changes, histological changes in the liver, vascular structures in the fin, and serum biochemical markers were evaluated in a time-dependent manner after treatment with selective peroxisome proliferator-activated receptor α modulator (pemafibrate), statin (pitavastatin), sodium-glucose cotransporter 2 inhibitor (tofogliflozin), and their combinations. Furthermore, to determine the mechanisms underlying the effects, whole transcriptome sequencing was conducted using medaka liver samples.ResultsHistological analyses revealed significant suppression of fat accumulation and fibrotic changes in the liver after treatment with drugs and their combinations. The expression levels of steatosis- and fibrosis-related genes were modified by the treatments. Moreover, the HFD-induced vascular damages in the fin exhibited milder changes after treatment with the drugs.ConclusionThe effects of treating various metabolic pathways on the medaka body, liver, and vascular structures of the NASH medaka model were evidenced. Moreover, to our knowledge, this study is the first to report whole genome sequence and gene expression evaluation of medaka livers, which could be helpful in clarifying the molecular mechanisms of drugs.