期刊
ENDOCRINOLOGY
卷 163, 期 7, 页码 -出版社
ENDOCRINE SOC
DOI: 10.1210/endocr/bqac072
关键词
liver X receptor; 27-hydroxycholesterol; nuclear receptor; breast cancer; myeloid cell; selective LXR modulator; SLiMs; SLXRM
资金
- National Cancer Institute of the National Institutes of Health [R01CA234025]
- Department of Defense Breast Cancer Research Program Era of Hope Scholar Award [W81XWH20-BCRP-EOHS/BC200206]
- American Institute for Cancer Research [713063]
- METAvivor
- National Heart, Lung, and Blood Institute of the National Institutes of Health [R35HL135799]
- Julie and David Mead Endowed Graduate Student Fellowship
- NIH Chemistry-Biology Interface Training Grant [T32-GM136629]
- University of Illinois School of Molecular and Cellular Biology Summer Undergraduate Research Fellowship
Dysregulation of cholesterol homeostasis is associated with various diseases. Liver X receptors (LXRs), as major regulators of cholesterol homeostasis, can be selectively modulated by different ligands, influencing multiple biological systems. This study provides evidence of LXR selective modulation through gene expression analysis, laying the foundation for developing precision pharmacology LXR ligands.
Dysregulation of cholesterol homeostasis is associated with many diseases such as cardiovascular disease and cancer. Liver X receptors (LXRs) are major upstream regulators of cholesterol homeostasis and are activated by endogenous cholesterol metabolites such as 27-hydroxycholesterol (27HC). LXRs 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 LXRs can be selectively modulated by different ligands. Here, we use RNA-sequencing of macrophages and single-cell RNA-sequencing of immune cells from metastasis-bearing murine lungs to provide evidence that LXR satisfies the 2 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 the cell or tissue type. The concept that the LXRs can be selectively modulated provides the foundation for developing precision pharmacology LXR ligands that are tailored to promote those activities that are desirable (proimmune), but at the same time minimizing harmful side effects (such as elevated triglyceride levels).
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