A study in Sweden, using mice and human liver cells, has identified a liver enzyme that may partly explain why men and women process cholesterol differently and show different risks of heart disease. 

Men are generally at a higher risk of developing atherosclerosis, the build-up of fatty plaques inside arteries that restrict blood flow. Since the liver plays a central role in controlling cholesterol and fat metabolism, researchers have been investigating the biological mechanisms behind these sex differences. 

A team at EARA member Karolinska Institutet studied KDM6A, a protein encoded on the X chromosome and naturally produced at higher levels in females. The researchers found that genetically altered female mice lacking KDM6A accumulated more cholesterol in the liver and developed more extensive atherosclerosis when fed a diet rich in fat and cholesterol. However, male mice with the same genetic alteration did not show any significant changes. 

The researchers also studied human liver cells and found that KDM6A works together with two other proteins, HNF4A and CREBH, to switch on genes involved in how the liver processes and transports cholesterol and fats in the body. 

“Taken together, our data show that an entire network of proteins in the liver regulates cholesterol metabolism in a way that differs between the sexes,” said Lin Chen, researcher at Karolinska Institutet and first author of the study published in Nature Communications.