The murine liver x receptor is selectively modulated by different ligands to differentially alter tumor-associated myeloid cells [bulk RNA-seq]

ABSTRACT: Dysregulation of cholesterol metabolism and homeostasis is associated with the pathology of many diseases such as cardiovascular disease and cancer. Two major upstream regulators of cholesterol homeostasis are the SREBP2 pathway and the actions of the liver X receptors (LXRs), with the liver thought to handle the majority of cholesterol homeostasis at the organismal level. Endogenous cholesterol metabolites such as 27-hydroxycholesterol (27HC), which serve to activate the nuclear receptor LXR, result in increased expression of genes associated with cholesterol catabolism and efflux. LXR and various LXR ligands such as 27HC have been described to influence several extra-hepatic biological systems. However, disparate reports of LXR function have emerged, especially with respect to immunology and cancer biology. This would suggest that similar to steroid nuclear receptors, the LXR may be selectively modulated by ligands. Here, we use bulk RNA-sequencing of bone marrow-derived macrophages and single-cell RNA-sequencing of immune cells from murine lungs bearing metastatic mammary cancer, to prove that LXR satisfies the two principles of selective nuclear receptor modulation: (1) different LXR ligands result in overlapping but distinct gene expression profiles within the same cell type, and (2) the same LXR ligands differentially regulate gene expression in a highly context-specific manner, depending on cell or tissue type. The concept that the LXR can be selectively modulated provides the foundation for the development of ligands that are tailored to promote those activities that are desirable (pro-immune), but at the same time minimizing harmful side effects (such as elevated triglyceride levels).

ORGANISM(S): Mus musculus

PROVIDER: GSE186909 | GEO | 2022/06/01

REPOSITORIES: GEO