Genome-wide analysis of LXRα activation reveals new transcriptional networks in human atherosclerotic foam cells

Nucleic Acids Res. 2013 Apr 1;41(6):3518-31. doi: 10.1093/nar/gkt034. Epub 2013 Feb 7.

Abstract

Increased physiological levels of oxysterols are major risk factors for developing atherosclerosis and cardiovascular disease. Lipid-loaded macrophages, termed foam cells, are important during the early development of atherosclerotic plaques. To pursue the hypothesis that ligand-based modulation of the nuclear receptor LXRα is crucial for cell homeostasis during atherosclerotic processes, we analysed genome-wide the action of LXRα in foam cells and macrophages. By integrating chromatin immunoprecipitation-sequencing (ChIP-seq) and gene expression profile analyses, we generated a highly stringent set of 186 LXRα target genes. Treatment with the nanomolar-binding ligand T0901317 and subsequent auto-regulatory LXRα activation resulted in sequence-dependent sharpening of the genome-binding patterns of LXRα. LXRα-binding loci that correlated with differential gene expression revealed 32 novel target genes with potential beneficial effects, which in part explained the implications of disease-associated genetic variation data. These observations identified highly integrated LXRα ligand-dependent transcriptional networks, including the APOE/C1/C4/C2-gene cluster, which contribute to the reversal of cholesterol efflux and the dampening of inflammation processes in foam cells to prevent atherogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism
  • Cell Line
  • Cells, Cultured
  • Cholesterol / metabolism
  • Foam Cells / drug effects
  • Foam Cells / metabolism*
  • Gene Expression Regulation
  • Gene Regulatory Networks*
  • Genetic Loci
  • Genetic Variation
  • Genome, Human
  • Humans
  • Hydrocarbons, Fluorinated / pharmacology
  • Ligands
  • Liver X Receptors
  • Macrophages / metabolism
  • Orphan Nuclear Receptors / agonists
  • Orphan Nuclear Receptors / metabolism*
  • PPAR alpha / metabolism
  • Signal Transduction
  • Sulfonamides / pharmacology
  • Transcription Initiation Site

Substances

  • Hydrocarbons, Fluorinated
  • Ligands
  • Liver X Receptors
  • NR1H3 protein, human
  • Orphan Nuclear Receptors
  • PPAR alpha
  • Sulfonamides
  • TO-901317
  • Cholesterol