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

Cell Stem Cell. 2017 Apr 6;20(4):478-489.e5. doi: 10.1016/j.stem.2017.01.011.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins B / metabolism
  • Cardiac Glycosides / pharmacology
  • Cardiac Glycosides / therapeutic use*
  • Cholesterol, LDL / blood
  • Drug Evaluation, Preclinical*
  • Hep G2 Cells
  • Hepatocytes / cytology*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Homozygote
  • Humans
  • Hypercholesterolemia / blood
  • Hypercholesterolemia / drug therapy*
  • Hypolipidemic Agents / chemistry
  • Hypolipidemic Agents / pharmacology
  • Hypolipidemic Agents / therapeutic use
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / metabolism
  • Mice
  • Mice, Inbred NOD
  • Proteolysis / drug effects
  • Small Molecule Libraries / pharmacology
  • Small Molecule Libraries / therapeutic use


  • Apolipoproteins B
  • Cardiac Glycosides
  • Cholesterol, LDL
  • Hypolipidemic Agents
  • Small Molecule Libraries