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

iPSC-derived hepatocytes are used to identify small molecule inhibitors of apoB secretion by the liver without causing steatosis. 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.

Automated summary

iPSC-derived hepatocytes were used to identify small molecule inhibitors of apoB secretion without causing steatosis. These inhibitors show effectiveness in reducing apoB secretion in cultured hepatocytes and humanized livers in mice. This research provides a potential solution for treating FH patients with hoFH mutations, with the identified small molecules having a distinct chemical structure from existing cholesterol lowering drugs.