Regulation of Cholesterol Homeostasis by a Novel Long Non-coding RNA LASER

Sci Rep. 2019 May 22;9(1):7693. doi: 10.1038/s41598-019-44195-2.

Abstract

Genome-wide association studies (GWAS) have identified many genetic variants in genes related to lipid metabolism. However, how these variations affect lipid levels remains elusive. Long non-coding RNAs (lncRNAs) have been implicated in a variety of biological processes. We hypothesize lncRNAs are likely to be located within disease or trait-associated DNA regions to regulate lipid metabolism. The aim of this study was to investigate whether and how lncRNAs in lipid- associated DNA regions regulate cholesterol homeostasis in hepatocytes. In this study, we identified a novel long non-coding RNA in Lipid Associated Single nucleotide polymorphism gEne Region (LASER) by bioinformatic analysis. We report that LASER is highly expressed in both hepatocytes and peripheral mononuclear cells (PBMCs). Clinical studies showed that LASER expression is positively related with that of cholesterol containing apolipoprotein levels. In particular, we found that LASER is positively correlated with plasma PCSK9 levels in statin free patients. siRNAs mediated knock down of LASER dramatically reduces intracellular cholesterol levels and affects the expression of genes involved in cholesterol metabolism. Transcriptome analyses show that knockdown of LASER affects the expression of genes involved in metabolism pathways. We found that HNF-1α and PCSK9 were reduced after LASER knock-down. Interestingly, the reduction of PCSK9 can be blocked by the treatment of berberine, a natural cholesterol-lowering compound which functions as a HNF-1α antagonist. Mechanistically, we found that LASER binds to LSD1 (lysine-specific demethylase 1), a member of CoREST/REST complex, in nucleus. LASER knock-down enhance LSD1 targeting to genomic loci, resulting in decreased histone H3 lysine 4 mono-methylation at the promoter regions of HNF-1α gene. Conversely, LSD1 knock-down abolished the effect of LASER on HNF-1α and PCSK9 expressions. Finally, we found that statin treatment increased LASER expression, accompanied with increased PCSK9 expression, suggesting a feedback regulation of cholesterol on LASER expression. This observation may partly explain the statin escape during anti-cholesterol treatment. These findings identified a novel lncRNA in cholesterol homeostasis. Therapeutic targeting LASER might be an effective approach to augment the effect of statins on cholesterol levels in clinics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticholesteremic Agents / pharmacology
  • Anticholesteremic Agents / therapeutic use
  • Apolipoproteins / metabolism
  • Atorvastatin / pharmacology
  • Atorvastatin / therapeutic use
  • Benzoates / pharmacology
  • Benzylamines / pharmacology
  • Berberine / pharmacology
  • Cholesterol / metabolism*
  • Chromosomes, Human, Pair 11 / genetics
  • Coronary Disease / drug therapy
  • Gene Expression Regulation
  • Genome-Wide Association Study
  • Hep G2 Cells
  • Hepatocyte Nuclear Factor 1-alpha / biosynthesis
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocytes / metabolism*
  • Histone Code / drug effects
  • Histone Demethylases / metabolism
  • Homeostasis / genetics
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Hypercholesterolemia / drug therapy
  • Hypercholesterolemia / metabolism
  • Leukocytes, Mononuclear / metabolism*
  • Proprotein Convertase 9 / biosynthesis
  • Proprotein Convertase 9 / genetics
  • Protein Binding
  • Protein Interaction Mapping
  • RNA Interference
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / physiology*
  • RNA, Small Interfering / genetics

Substances

  • Anticholesteremic Agents
  • Apolipoproteins
  • Benzoates
  • Benzylamines
  • GW 3965
  • HNF1A protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • RNA, Long Noncoding
  • RNA, Small Interfering
  • Berberine
  • Cholesterol
  • Atorvastatin
  • Histone Demethylases
  • KDM1A protein, human
  • PCSK9 protein, human
  • Proprotein Convertase 9