LXR Is Selectively Modulated in Myeloid Cells

Liqian Ma, Hashni Epa Vidana Gamage, Srishti Tiwari, Chaeyeon Han, Madeline A Henn, Natalia Krawczynska, Payam Dibaeinia, Graeme J Koelwyn, Anasuya Das Gupta, Rafael Ovidio Bautista Rivas, Chris L Wright, Fangxiu Xu, Kathryn J Moore, Saurabh Sinha, Erik R Nelson
Endocrinology, Volume 163, Issue 7, July 2022, bqac072
https://doi.org/10.1210/endocr/bqac072

Abstract

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).

You may also like...