Human hepatic in vitro models reveal distinct anti-NASH potencies of PPAR agonists
Human hepatic in vitro models reveal distinct anti-NASH potencies of PPAR agonists
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DOI：
10.1007/s10565-020-09544-2
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发表时间：
2020-07-01
影响因子：
6.1
通讯作者：
Rodrigues, Robim M.
中科院分区：
文献类型：
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作者：
Boeckmans, Joost;Natale, Alessandra;Rodrigues, Robim M.
非酒精性脂肪性肝炎(NASH)是一种以肝脏脂肪堆积、炎症和伴随的纤维化为特征的高度流行的慢性肝病。到目前为止，还没有批准任何抗NASH药物。在这项研究中，我们通过将原代人肝细胞(PHH)、人皮肤干细胞来源的肝细胞(hSKP-HPC)、HepaRG和HepG2细胞系以及LX-2细胞暴露于多种在NASH发生中起作用的因素，在体外复制了NASH的关键特征。所获得的体外疾病模型显示细胞内脂质堆积，分泌炎性趋化因子，诱导ATP含量，细胞凋亡，并增加促纤维化基因的表达。然后，这些细胞系统被用来评估八种过氧化物酶体增殖物激活受体(PPAR)激动剂(苯扎贝特、伊拉非贝诺、非诺贝特、拉尼贝诺、培马贝特、吡格列酮、罗格列酮和沙格列酮)的抗NASH特性。PPAR激动剂不同程度地抑制脂质堆积、炎性趋化因子的分泌和促纤维化基因的表达。基于获得的读数，开发了一个评分系统来对反纳什效力进行评级。基于一系列最好的模型，即PHH，hSKP-HPC和LX-2培养的体外评分系统显示，Elafibror，其次是Saroglitazar和Pioglitazone，诱导了最强的抗NASH作用。这些数据证实了现有的临床数据，并显示了这些体外模型与抗NASH化合物的临床前研究的相关性。
Non-alcoholic steatohepatitis (NASH) is a highly prevalent, chronic liver disease characterized by hepatic lipid accumulation, inflammation, and concomitant fibrosis. Up to date, no anti-NASH drugs have been approved. In this study, we reproduced key NASH characteristics in vitro by exposing primary human hepatocytes (PHH), human skin stem cell-derived hepatic cells (hSKP-HPC), HepaRG and HepG2 cell lines, as well as LX-2 cells to multiple factors that play a role in the onset of NASH. The obtained in vitro disease models showed intracellular lipid accumulation, secretion of inflammatory chemokines, induced ATP content, apoptosis, and increased pro-fibrotic gene expression. These cell systems were then used to evaluate the anti-NASH properties of eight peroxisome proliferator-activated receptor (PPAR) agonists (bezafibrate, elafibranor, fenofibrate, lanifibranor, pemafibrate, pioglitazone, rosiglitazone, and saroglitazar). PPAR agonists differently attenuated lipid accumulation, inflammatory chemokine secretion, and pro-fibrotic gene expression. Based on the obtained readouts, a scoring system was developed to grade the anti-NASH potencies. The in vitro scoring system, based on a battery of the most performant models, namely PHH, hSKP-HPC, and LX-2 cultures, showed that elafibranor, followed by saroglitazar and pioglitazone, induced the strongest anti-NASH effects. These data corroborate available clinical data and show the relevance of these in vitro models for the preclinical investigation of anti-NASH compounds.