@article{f2d7620a3547408da8d35216667b9ec6,
title = "A Drug Screen using Human iPSC-Derived Hepatocyte-like Cells Reveals Cardiac Glycosides as a Potential Treatment for Hypercholesterolemia",
abstract = "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.",
keywords = "drug screen, hepatocytes, hypercholesterolemia, induced pluripotent stem cells, metabolic liver disease",
author = "Cayo, {Max A.} and Mallanna, {Sunil K.} and {Di Furio}, Francesca and Ran Jing and Tolliver, {Lauren B.} and Matthew Bures and Amanda Urick and Noto, {Fallon K.} and Pashos, {Evanthia E.} and Greseth, {Matthew D.} and Maciej Czarnecki and Paula Traktman and Wenli Yang and Morrisey, {Edward E.} and Markus Grompe and Rader, {Daniel J.} and Duncan, {Stephen A.}",
note = "Funding Information: This work was supported by the NIH grants DK55743, DK087377, DK102716 (S.A.D.), HG006398 (to S.A.D. and D.J.R.), and F30 DK091994 (to M.A.C.). Additional support was received from the Keck Foundation, the Phoebe R. and John D. Lewis Foundation, the Marcus Family, and the Sophia Wolf Quadracci Memorial Fund. Glenn Bushee provided valuable advice for the analyses of electronic medical records that was supported by the Medical College of Wisconsin CTSA grant 8UL1TR000055 and the Advancing a Healthier Wisconsin endowment at the Medical College of Wisconsin. Human hepatocytes were provided as a generous gift from Thermo Fisher Scientific, Life Technologies. Lisa Wilson and John Bial from the Yecuris Corporation provided expert advice and guidance in repopulation of FRGN mice with human hepatocytes. OHSU and Dr. Grompe have a significant financial interest in Yecuris, Inc., a company that may have a commercial interest in the results of this research and technology. This potential conflict of interest has been reviewed and managed by OHSU. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = apr,
day = "6",
doi = "10.1016/j.stem.2017.01.011",
language = "English (US)",
volume = "20",
pages = "478--489.e5",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "4",
}