December 21, 2020 9:38 AM

New Gene Target Could Improve Cholesterol Without Harming the Liver

Preclinical study identifies possible therapeutic target for cardiovascular risk factors that avoid the common problem of an increased risk of fatty liver disease.

gene drawing in blue ink on lined paper
Image by Stephanie King.

Medications to improve cholesterol and reduce cardiovascular risk factors can also put some patients at a higher risk for fatty liver disease or liver damage.

A new study from an international team of researchers points to a few genes as possible future targets to address cardiovascular risk without affecting the liver or causing other metabolic disorders.

“We know that some genes/proteins cause your cholesterol to either clog up your arteries or clog up your liver. We wanted to find genes that help people avoid it all: heart disease, diabetes and liver disease,” explains co-corresponding author Cristen Willer, Ph.D., an associate professor of internal medicine, human genetics and computational medicine and bioinformatics, from the Michigan Medicine Frankel Cardiovascular Center.

Willer and colleagues identified 76 notable variants with potential, 11 of which were previously unreported. She says one in particular, known as ZNF529, was particularly interesting. People missing one copy of that gene had lower LDL cholesterol measures.

When the researchers in Y. Eugene Chen’s Frankel CVC lab examined the gene in human liver cells, it had the same effect as a popular class of cholesterol-lowering drugs, PCSK9 inhibitors, that upregulate or activate the LDL receptor.

The researchers suggest future research to investigate inhibiting ZNF529. They also note this gene does not exist in mice, which limits the ability to study this gene in mice, but also suggests that mammals can survive without this gene.

“Understanding genes and genetic variants impacting the risk of CVD in the context of their biological roles will allow better choices for drug targets that will be more effective at preventing and treating disease, with fewer side effects,” says co-corresponding author Chen, M.D., Ph.D., a professor of internal medicine, cardiac surgery, physiology, pharmacology and medicinal chemistry.

Paper cited: “Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease.” Nature Communications. DOI: 10.1038/s41467-020-20086-3