Control of LDL uptake in human cells by targeting the LDLR regulatory long non-coding RNA BM450697

Abstract Hypercholesterolemia is a condition, which is characterized by very high levels of cholesterol in the blood and is a major correlating factor involved in heart disease. Indeed, high levels of the low density lipoprotein (LDL) have been causally linked to the development of atherosclerotic cardiovascular disease (ASCVD). A method to specifically reduce cholesterol in the blood in a long term and stable manner could prove therapeutically relevant. Cholesterol is removed from the blood by the Low-density lipoprotein receptor (LDLR) in the liver. Others and we have discovered that a long non-coding RNA, (BM450697), functions as an endogenous epigenetic regulator of LDLR, and that the repression of this lncRNA, by the action of small interfering RNAs (siRNAs), results in the activation of LDLR. We find here, through the interrogation of two siRNAs that can target this lncRNA both in a transcriptional and post-transcriptional manner, that BM450697 functions as a local scaffold to modulate LDLR transcription. Moreover, we find that conjugation of GalNAc to two lncRNA directed siRNAs allows for direct liver cell targeting of this lncRNA and functional enhanced uptake of cholesterol. Collectively, these data suggest that targeting the BM450697 lncRNA regulator of LDLR may result in a more specific and long-term targeted approach to regulating cholesterol in the blood.