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Using Human Induced Pluripotent Stem Cell-derived Hepatocyte-like Cells for Drug Discovery
Published on: May 19, 2018
A human iPSC-derived hepatocyte screen identifies compounds that inhibit production of Apolipoprotein B
Jui-Tung Liu1, Caren Doueiry1, Yu-Lin Jiang1
1Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, 29425, USA.
Insights
Researchers discovered novel small molecules that effectively lower apolipoprotein B (apoB) levels in familial hypercholesterolemia (FH) patients. These compounds offer a safer alternative to existing treatments by avoiding liver fat accumulation and elevated enzymes.
Area of Science:
- Biochemistry
- Pharmacology
- Genetics
Background:
- Familial hypercholesterolemia (FH) involves high LDL-C, leading to cardiovascular disease.
- Current FH treatments, especially for homozygous LDLR mutations (hoFH), are often insufficient.
- Existing hoFH drugs can cause adverse effects like liver triglyceride accumulation and hepatic steatosis.
Purpose of the Study:
- To identify novel, safer small molecules for treating FH.
- To find compounds that reduce apolipoprotein B (apoB) secretion without causing liver lipid accumulation.
Main Methods:
- Screening of 10,000 small molecules from a 130,000-compound library.
- Utilizing an induced pluripotent stem cell (iPSC)-derived hepatocyte platform.
- Testing efficacy in cultured hepatocytes and humanized mouse liver models.
Main Results:
- Identified small molecules that significantly reduce apoB secretion.
- Demonstrated effectiveness in both in vitro and in vivo models.
- Observed no abnormal lipid accumulation in the liver.
- Discovered compounds with a distinct chemical structure from existing cholesterol-lowering drugs.
Conclusions:
- Novel small molecules effectively lower apoB secretion, a key target in FH.
- These compounds represent a promising, safer therapeutic approach for hoFH.
- The distinct chemical structure may offer a new class of cholesterol-lowering drugs.
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.
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