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

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

Research output: Contribution to journalArticle

39 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)478-489.e5
JournalCell Stem Cell
Volume20
Issue number4
DOIs
StatePublished - Apr 6 2017

Keywords

  • drug screen
  • hepatocytes
  • hypercholesterolemia
  • induced pluripotent stem cells
  • metabolic liver disease

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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    Cayo, M. A., Mallanna, S. K., Di Furio, F., Jing, R., Tolliver, L. B., Bures, M., Urick, A., Noto, F. K., Pashos, E. E., Greseth, M. D., Czarnecki, M., Traktman, P., Yang, W., Morrisey, E. E., Grompe, M., Rader, D. J., & Duncan, S. A. (2017). A Drug Screen using Human iPSC-Derived Hepatocyte-like Cells Reveals Cardiac Glycosides as a Potential Treatment for Hypercholesterolemia. Cell Stem Cell, 20(4), 478-489.e5. https://doi.org/10.1016/j.stem.2017.01.011