A human iPSC-derived hepatocyte screen identifies compounds that inhibit production of Apolipoprotein B.

Autor: Liu JT; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, 29425, USA., Doueiry C; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, 29425, USA., Jiang YL; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, 29425, USA., Blaszkiewicz J; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, 29425, USA., Lamprecht MP; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, 29425, USA., Heslop JA; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, 29425, USA., Peterson YK; Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA., Carten JD; Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, 29425, USA., Traktman P; Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, 29425, USA., Yuan Y; Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL, 60607, USA., Khetani SR; Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL, 60607, USA., Twal WO; Grùthan Biosciences LLC, Hollywood, SC, 29449, USA., Duncan SA; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, 29425, USA. duncanst@musc.edu.; Grùthan Biosciences LLC, Hollywood, SC, 29449, USA. duncanst@musc.edu.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2023 Apr 24; Vol. 6 (1), pp. 452. Date of Electronic Publication: 2023 Apr 24.
DOI: 10.1038/s42003-023-04739-9
Abstrakt: Familial hypercholesterolemia (FH) patients suffer from excessively high levels of Low Density Lipoprotein Cholesterol (LDL-C), which can cause severe cardiovascular disease. Statins, bile acid sequestrants, PCSK9 inhibitors, and cholesterol absorption inhibitors are all inefficient at treating FH patients with homozygous LDLR gene mutations (hoFH). Drugs approved for hoFH treatment control lipoprotein production by regulating steady-state Apolipoprotein B (apoB) levels. Unfortunately, these drugs have side effects including accumulation of liver triglycerides, hepatic steatosis, and elevated liver enzyme levels. To identify safer compounds, we used an iPSC-derived hepatocyte platform to screen a structurally representative set of 10,000 small molecules from a proprietary library of 130,000 compounds. The screen revealed molecules that could reduce the secretion of apoB from cultured hepatocytes and from humanized livers in mice. These small molecules are highly effective, do not cause abnormal lipid accumulation, and share a chemical structure that is distinct from any known cholesterol lowering drug.
(© 2023. The Author(s).)
Databáze: MEDLINE
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