A Novel Y-Specifc Long NonCoding RNA Associated with Cellular Lipid Accumulation in HepG2 cells and Atherosclerosisrelated Genes

There is an increasing appreciation for the role of the human Y chromosome in phenotypic diferences between the sexes in health and disease. Previous studies have shown that genetic variation within the Y chromosome is associated with cholesterol levels, which is an established risk factor for atherosclerosis, the underlying cause of coronary artery disease (CAD), a major cause of morbidity and mortality worldwide. However, the exact mechanism and potential genes implicated are still unidentifed. To date, Y chromosome-linked long non-coding RNAs (lncRNAs) are poorly characterized and the potential link between these new regulatory RNA molecules and hepatic function in men has not been investigated. Advanced technologies of lncRNA subcellular localization and silencing were used to identify a novel intergenic Y-linked lncRNA, named lnc-KDM5D-4, and investigate its role in fatty liver-associated atherosclerosis. We found that lnc-KDM5D-4 is retained within the nucleus in hepatocytes. Its knockdown leads to changes in genes leading to increased lipid droplets formation in hepatocytes resulting in a downstream efect contributing to the chronic infammatory process that underpin CAD. Our fndings provide the frst evidence for the implication of lnc-KDM5D-4 in key processes related to fatty liver and cellular infammation associated with atherosclerosis and CAD in men.