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

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.

Human induced pluripotent stem cells‐derived liver organoids grown on a Biomimesys® hyaluronic acid‐based hydroscaffold as a new model for studying human lipoprotein metabolism

“…The development of protocols aiming at differentiating hiPSC into liver cells has, however, provided an almost inexhaustible source of hepatocytes. 14 In particular, we 3 and others, 30 have developed models of hiPSCs differentiated into HLCs to study the metabolism of lipoproteins. A known limitation of these models is that HLCs keep residual characteristics of fetal or neonatal hepatocytes, with persistent expression of alpha‐fetoprotein and low albumin production.…”