A human iPSC-derived hepatocyte screen identifies compounds that inhibit production of Apolipoprotein B
Year: 2023
Type: article
Abstract: 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.
Source: Communications Biology
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,690
Funders: U.S. Department of Health and Human Services, Medical University of South Carolina, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1310919184, G154054316, G1551817834, G2946007580, G3068391078, G462846151, G482447884, G5059225990, G6125222235, G6224975242, Molecular Basis of Human Hepatic Progenitor Cell Formation, Analysis of new compounds to treat familial hypercholesterolemia, G8442482983, G8647119954, Study and Treatment of Mitochondrial DNA Depletion Syndrome 3 Using iPSCs, G9000204985, G9000233351, G9000287593, Inhibition of hepatic (V)LDL production by a novel antagonist of carboxyl esterase 1, COBRE in Digestive and Liver Disease, Digestive Disease Training Program, Medical University of South Carolina - Cancer Center Support Grant, MUSC Digestive Disease Research Core Center, G974618274
OpenAlex ID: W4366816178