A Drug Screen using Human iPSC-Derived Hepatocyte-like Cells Reveals Cardiac Glycosides as a Potential Treatment for Hypercholesterolemia

Publication date: 6 April 2017
Source:Cell Stem Cell, Volume 20, Issue 4
Author(s): Max A. Cayo, Sunil K. Mallanna, Francesca Di Furio, Ran Jing, Lauren B. Tolliver, Matthew Bures, Amanda Urick, Fallon K. Noto, Evanthia E. Pashos, Matthew D. Greseth, Maciej Czarnecki, Paula Traktman, Wenli Yang, Edward E. Morrisey, Markus Grompe, Daniel J. Rader, Stephen A. Duncan
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.

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Teaser

Cayo et al. of the NHLBI NextGen consortium use hepatocytes from familial hypercholesterolemia iPSCs in a drug screen that highlights cardiac glycosides as a candidate treatment acting to reduce apoB levels via proteolytic turnover and as a result lower LDL-C.


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