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

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 fam...

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Bibliographic Details
Published in:Cell stem cell 2017-04, Vol.20 (4), p.478-489.e5
Main Authors: Cayo, Max A., Mallanna, Sunil K., Di Furio, Francesca, Jing, Ran, Tolliver, Lauren B., Bures, Matthew, Urick, Amanda, Noto, Fallon K., Pashos, Evanthia E., Greseth, Matthew D., Czarnecki, Maciej, Traktman, Paula, Yang, Wenli, Morrisey, Edward E., Grompe, Markus, Rader, Daniel J., Duncan, Stephen A.
Format: Article
Language:English
Subjects:
Animals
Apolipoproteins B - metabolism
Cardiac Glycosides - pharmacology
Cardiac Glycosides - therapeutic use
Cholesterol, LDL - blood
Drug Evaluation, Preclinical
drug screen
Hep G2 Cells
hepatocytes
Hepatocytes - cytology
Hepatocytes - drug effects
Hepatocytes - metabolism
Homozygote
Humans
hypercholesterolemia
Hypercholesterolemia - blood
Hypercholesterolemia - drug therapy
Hypolipidemic Agents - chemistry
Hypolipidemic Agents - pharmacology
Hypolipidemic Agents - therapeutic use
induced pluripotent stem cells
Induced Pluripotent Stem Cells - cytology
Induced Pluripotent Stem Cells - drug effects
Induced Pluripotent Stem Cells - metabolism
metabolic liver disease
Mice
Mice, Inbred NOD
Proteolysis - drug effects
Small Molecule Libraries - pharmacology
Small Molecule Libraries - therapeutic use
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Summary: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. [Display omitted] •HoFH iPSC-derived hepatocytes provide a platform to identify LDL-C-lowering drugs•Screening reveals that cardiac glycosides can reduce hepatocyte production of apoB•ApoB reduction occurs via increased proteolytic turnover•Cardiac glycoside treatment reduces serum LDL-C in patients and humanized mice 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.
ISSN:1934-5909
1875-9777
DOI:10.1016/j.stem.2017.01.011