Elafibranor restricts lipogenic and inflammatory responses in a human skin stem cell-derived model of NASH
Elafibranor restricts lipogenic and inflammatory responses in a human skin stem cell-derived model of NASH
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DOI：
10.1016/j.phrs.2019.04.016
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发表时间：
2019-06-01
影响因子：
9.3
通讯作者：
Vanhaecke, Tamara
中科院分区：
文献类型：
--
作者：
Boeckmans, Joost;Buyl, Karolien;Vanhaecke, Tamara
非酒精性脂肪性肝炎（NASH）的特征是肝细胞脂肪变性伴肝脏炎症。尽管其大流行的比例，没有抗NASH药物已被批准。这部分是因为药物开发是减速由于缺乏足够的工具来评估潜在的新药物candides.The本研究的疗效描述了一种新的NASH临床前模型的开发和应用所产生的肝细胞从人类皮肤来源的前体。将这些细胞暴露于脂肪生成（胰岛素、葡萄糖、脂肪酸）和促炎因子细胞因子（IL-1 β、TNF-α、TGF-β）的作用导致特征性NASH应答，如细胞内脂质积累、NASH特异性基因表达的调节、增加的半胱天冬酶-3/7活性和炎性标志物（包括CCL 2、CCL 5、CCL 7、CCL 8、CXCL 5、CXCL 8、CXCL 9、CXCL 10、CXCL 11、CXCL 12、CXCL 13、CXCL 14、CXCL 15、CXCL 16、CXCL 17、CXCL 18、CXCL 19、CXCL 18、CXCL 1 IL 1a、IL 6和IL 11。通过转录组学分析证实了所提出的NASH模型的人类相关性，该分析揭示了共同调控的基因，并鉴定了体外系统与患有NASH的患者之间的相同基因类别。通过测试目前正在进行临床III期试验评估的有前途的抗NASH化合物elafibranor，证明了该体外模型的应用潜力。Elafibranor在体外减弱NASH的关键特征，并显著降低脂质负荷以及炎症趋化因子的表达和分泌，其在体内负责免疫细胞的募集。这种炎症反应的减少是NM介导的。总之，这种人类相关的体外系统被证明是研究新型抗NASH化合物的灵敏测试工具。
Non-alcoholic steatohepatitis (NASH) is characterized by hepatocellular steatosis with concomitant hepatic inflammation. Despite its pandemic proportions, no anti-NASH drugs have been approved yet. This is partially because drug development is decelerated due to the lack of adequate tools to assess the efficacy of potential new drug candidates.The present study describes the development and application of a new preclinical model for NASH using hepatic cells generated from human skin-derived precursors. Exposure of these cells to lipogenic (insulin, glucose, fatty acids) and pro-inflammatory factors (IL-1 beta, TNF-alpha, TGF-beta) resulted in a characteristic NASH response, as indicated by intracellular lipid accumulation, modulation of NASH-specific gene expression, increased caspase-3/7 activity and the expression and/or secretion of inflammatory markers, including CCL2, CCL5, CCL7, CCL8, CXCL5, CXCL8, IL1a, IL6 and IL11.The human relevance of the proposed NASH model was verified by transcriptomics analyses that revealed commonly modulated genes and the Identification of the same gene classes between the in vitro system and patients suffering from NASH.The application potential of this in vitro model was demonstrated by testing elafibranor, a promising anti-NASH compound currently under clinical phase III trial evaluation. Elafibranor attenuated in vitro key features of NASH, and dramatically lowered lipid load as well as the expression and secretion of inflammatory chemokines, which in vivo are responsible for the recruitment of immune cells. This reduction in inflammatory response was NM-mediated. In summary, this human-relevant, in vitro system proved to be a sensitive testing tool for the investigation of novel anti-NASH compounds.