AI Article Synopsis
- Most patients with familial hypercholesterolemia (FH) have dangerously high levels of LDL cholesterol, which increases their risk for serious heart issues.
- Current treatments for patients with the homozygous LDLR gene mutations (hoFH), like statins and PCSK9 inhibitors, are often ineffective and can cause harmful side effects, such as liver problems.
- Researchers screened 10,000 small molecules using an advanced liver cell model and discovered new compounds that effectively reduce ApoB secretion without causing lipid buildup, showing promise as safer alternatives to existing cholesterol-lowering drugs.
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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10125972 | PMC |
| http://dx.doi.org/10.1038/s42003-023-04739-9 | DOI Listing |
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