A Novel Y-Specific Long Non-Coding RNA Associated with Cellular Lipid Accumulation in HepG2 cells and Atherosclerosis-related Genes

Elsa Molina,Stephen A Myers,Maciej Tomaszewski,Elyse M Clarence,Guat S Chew,Fadi J Charchar,James M Eales

doi:10.1038/s41598-017-17165-9

Abstract

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. 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 effect contributing to the chronic inflammatory process that underpin CAD. Our 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.

Highlights

There is an increasing appreciation for the role of the human Y chromosome in phenotypic differences between the sexes in health and disease
Our findings demonstrate that lnc-KDM5D-4 is a nuclear-retained lincRNA that has a regulatory effect on the mRNA expression of genes such as Perilipin 2 (PLIN2), that in turn, lead to increased lipid droplets formation in hepatocytes
This study provides the first evidence of the expression of Y-linked lincRNA transcripts such as lnc-KDM5D-4:1, lnc-ZFY-1:1, lnc-ZFY-2:1, lnc-RBMY1B-1:1, lnc-RBMY1B-1:4, lnc-USP9Y-1:4, and lnc-HSFY2-3:6 in human hepatocellular carcinoma (HCC)

Summary

Introduction

There is an increasing appreciation for the role of the human Y chromosome in phenotypic differences between the sexes in health and disease. We studied for the first time eleven novel Y-linked lincRNAs by real-time PCR gene expression analysis in the human hepatoma HepG2 male cell line, an in vitro model system used in previous studies on liver steatosis The effects of fatty acid palmitate on the transcript expression of Y chromosome-linked lincRNAs in a steatosis HepG2 cell line.

Results

Conclusion