First evidence for the implication of lncRNA in key processes related to fatty liver and cellular inflammation associated with atherosclerosis

There is an increasing appreciation for the role of the human Y chromosome in phenotypic differences 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 unidentified. 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.

Researchers at Federation University, Australia used advanced technologies of lncRNA subcellular localization and silencing to identify a novel intergenic Y-linked lncRNA, named lnc-KDM5D-4, and investigate its role in fatty liver-associated atherosclerosis. They 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 effect contributing to the chronic inflammatory process that underpin CAD. These findings provide the first evidence for the implication of lnc-KDM5D-4 in key processes related to fatty liver and cellular inflammation associated with atherosclerosis and CAD in men.

Schematic diagram illustrating the potential role of lnc-KDM5D-4 in atherosclerosis


Atherosclerosis is driven by a chronic inflammatory process. Lipid disturbances and other risk factors are thought to cause endothelial injury resulting in monocyte adhesion and migration to the intima, as well as the release of cytokines and growth factors. Low-density lipoprotein (LDL) particles travelling in the blood and carrying cholesterol and triglycerides from the liver to other body tissues get through the endothelium layer due to their size and density, and become oxidized. After migration to the sub-endothelial space, monocytes differentiate into macrophages, which are then able to ingest oxidized-LDL, forming specialized foam cells. Macrophages are not able to process the oxidized-LDL and ultimately grow and rupture depositing a greater amount of oxidized cholesterol into the artery wall. This triggers the recruitment of more monocytes, thus increasing the inflammation and continuing the cycle. This inflammation leads to subendothelial accumulation of fatty substances called atheromatous plaques. In the hepatocytes, the underexpression of the Y chromosome-linked lincRNA lnc-KDM5D-4 results in an overexpression of the gene perilipin 2 (PLIN2) involved in lipid droplet formation within the cells. This increase of expression of PLIN2 may consequently initiates the ‘fatty liver’ or hepatic steatosis promoting atherosclerosis in the coronary arteries of men.

Molina E, Chew GS, Myers SA, Clarence EM, Eales JM, Tomaszewski M, Charchar FJ. (2017) A Novel Y-Specific Long Non-Coding RNA Associated with Cellular Lipid Accumulation in HepG2 cells and Atherosclerosis-related Genes. Sci Rep 7(1):16710. [article]

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