Genome-wide analysis of LXR? activation reveals new transcriptional networks in human atherosclerotic foam cells.

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 LXR? is crucial for cell homeostasis during atherosclerotic processes, we analysed genome-wide the action of LXR? 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 LXR? target genes. Treatment with the nanomolar-binding ligand T0901317 and subsequent auto-regulatory LXR? activation resulted in sequence-dependent sharpening of the genome-binding patterns of LXR?. LXR?-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 LXR? 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.

SUBMITTER: Feldmann R 

PROVIDER: S-EPMC3616743 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature