Abstract 14: Identification of Linc-OSBPL6 as a Competing Endogenous RNA that Regulates Cholesterol Homeostasis
Long non-coding RNAs (lncRNAs) have emerged as important regulators of gene expression in diverse biological contexts. Although several thousand lncRNAs have been identified in humans, only a small number have been fully characterized. Here we identify a novel human lncRNA, linc-OSBPL6, that functions as a competing endogenous RNA to regulate cellular cholesterol homeostasis. Linc-OSBPL6 has 7 variants that are broadly expressed in various cell types and tissues, and are controlled at the transcriptional level by the cholesterol-sensing nuclear receptor liver X receptor. We noted that each of the linc-OSBPL6 variants harbors binding sites for miR-27b and miR-33a/b, microRNAs recently identified as hubs controlling the expression of genes involved in cellular cholesterol efflux and HDL metabolism. Using linc-OSBPL6 knockdown and overexpression, combined with RNA profiling, we demonstrate that linc-OSBPL6 acts as a ‘microRNA sponge’ to limit availability of miR-27b and miR33a/b and inversely regulate expression of their target genes (ABCA1, OSBPL6, ANGPTL3, CROT, ABCB11). Consistent with the role of miR-27b and miR-33a/b in repressing cellular cholesterol export, we show that overexpression of linc-OSBPL6 increases cholesterol efflux, while shRNA-silencing of linc-OSBPL6 reduces cholesterol efflux from hepatocytes and macrophages. As cholesterol efflux in the liver plays a central role in HDL biogenesis, we investigated the relationship of hepatic linc-OSBPL6 to its microRNA-targets and plasma levels of HDL cholesterol in a cohort of 200 healthy individuals. We found that expression of linc-OSBPL6 is negatively correlated with levels of miR-27b and miR-33a/b in the liver, and positively correlated with levels of their target genes and plasma HDL cholesterol. These findings identify linc-OSBPL6 as a key regulatory component of the non-coding RNA circuitry that controls cellular cholesterol efflux and plasma HDL levels in humans.
Author Disclosures: C. van Solingen: None. E.J. Hennessy: None. M. Ouimet: None. K. Rinehold: None. M. Hussein: None. M.J. Garabedian: None. D. Teupser: None. L.M. Holdt: None. K.J. Moore: None.
This research has received full or partial funding support from the American Heart Association.
- © 2015 by American Heart Association, Inc.