A Drug Screen using Human iPSC-Derived Hepatocyte-like Cells Reveals Cardiac Glycosides as a Potential Treatment for Hypercholesterolemia
A Drug Screen using Human iPSC-Derived Hepatocyte-like Cells Reveals Cardiac Glycosides as a Potential Treatment for Hypercholesterolemia
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DOI：
10.1016/j.stem.2017.01.011
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发表时间：
2017-04-06
期刊：
影响因子：
23.9
通讯作者：
Duncan, Stephen A.
中科院分区：
文献类型：
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作者：
Cayo, Max A.;Mallanna, Sunil K.;Duncan, Stephen A.
由于缺乏模型，识别治疗遗传性代谢性肝病的药物的努力受到阻碍。然而，具有肝细胞特征的细胞可以由诱导多能干细胞（iPSC）产生。在这里，我们使用了从纯合子家族性高胆固醇血症（hoFH）iPSC产生的肝细胞样细胞来鉴定可以潜在地用于降低血清LDL-C的药物。我们发现，强心苷减少载脂蛋白B（apo B）从培养的人肝细胞和avatar小鼠的人源化肝脏的血清的生产。这些药物通过增加apoB蛋白的周转而起作用。对患者病历的分析显示，强心苷治疗患者可降低血清LDL-C水平。这些研究强调了使用iPSCs筛选先天性肝代谢缺陷的潜在治疗方法的有效性，并表明强心苷可以提供一种减少肝细胞apoB产生和治疗高胆固醇血症的方法。
Efforts to identify pharmaceuticals to treat heritable metabolic liver diseases have been hampered by the lack of models. However, cells with hepatocyte characteristics can be produced from induced pluripotent stem cells (iPSCs). Here, we have used hepatocyte-like cells generated from homozygous familial hypercholesterolemia (hoFH) iPSCs to identify drugs that can potentially be repurposed to lower serum LDL-C. We found that cardiac glycosides reduce the production of apolipoprotein B (apoB) from human hepatocytes in culture and the serum of avatar mice harboring humanized livers. The drugs act by increasing the turnover of apoB protein. Analyses of patient medical records revealed that the treatment of patients with cardiac glycosides reduced serum LDL-C levels. These studies highlight the effectiveness of using iPSCs to screen for potential treatments for inborn errors of hepatic metabolism and suggest that cardiac glycosides could provide an approach for reducing hepatocyte production of apoB and treating hypercholesterolemia.