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.
authors.affiliation: Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Max A
authors.initials: MA
authors.lastname: Cayo
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Mallanna
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Di Furio
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA.
authors.forename: Ran
authors.initials: R
authors.lastname: Jing
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA.
authors.forename: Lauren B
authors.initials: LB
authors.lastname: Tolliver
authors.affiliation: Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bures
authors.affiliation: Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Urick
authors.affiliation: Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Fallon K
authors.initials: FK
authors.lastname: Noto
authors.affiliation: Departments of Medicine and Genetics and the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Evanthia E
authors.initials: EE
authors.lastname: Pashos
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Greseth
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA; Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Maciej
authors.initials: M
authors.lastname: Czarnecki
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA; Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, MSC 955, Charleston, SC 29425, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Traktman
authors.affiliation: Department of Medicine and Penn Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Wenli
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Medicine and Penn Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Morrisey
authors.affiliation: Papé Family Pediatric Research Institute, Oregon Health & Science University, 3181 South West Sam Jackson Park Road/L321, Portland, OR 97239, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Grompe
authors.affiliation: Departments of Medicine and Genetics and the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.affiliation: Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, MSC 955, Charleston, SC 29425, USA. Electronic address: duncanst@musc.edu.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Duncan
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D002301:Cardiac Glycosides / Q000494:pharmacology / Q000627:therapeutic use*; D008078:Cholesterol, LDL / Q000097:blood; D004353:Drug Evaluation, Preclinical; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy*; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D059748:Proteolysis / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D001055:Apolipoproteins B; D002301:Cardiac Glycosides; D008078:Cholesterol, LDL; D000960:Hypolipidemic Agents; D054852:Small Molecule Libraries
keywords: drug screen; hepatocytes; hypercholesterolemia; induced pluripotent stem cells; metabolic liver disease