Nuclear receptors, cholesterol homeostasis and the immune system

Abstract

Cholesterol is essential for maintaining membrane fluidity in eukaryotes. Additionally, the synthetic cascade of cholesterol results in precursor molecules important for cellular function such as lipid raft formation and protein prenylation. As such, cholesterol homeostasis is tightly regulated. Interestingly, it is now known that some cholesterol precursors and many metabolites serve as active signaling molecules, binding to different classes of receptors including the nuclear receptors. Furthermore, many cholesterol metabolites or their nuclear receptors have been implicated in the regulation of the immune system in normal physiology and disease. Therefore, in this focused review, cholesterol homeostasis and nuclear receptors involved in this regulation will be discussed, with particular emphasis on how these cascades influence the immune system.

Keywords: Bile acids; Cholesterol; Homeostasis; Immune system; Nuclear receptors; Oxysterols.

Figure 1:. Cholesterol Metabolism, Nuclear Receptors, Immune Outcomes and Pathophysiology of Disease.

Cholesterol precursors, cholesterol itself and downstream metabolites affect myeloid and lymphoid immune cells, triggering or resolving a pro-inflammatory state. These effects are mediated by membrane receptors (such as CXCR2, Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2/GPR183), GPR17 or Smoothened), nuclear receptors (such as the LXRs for oxysterols and FXR in the case of bile acids), SREBPs (in the case of cholesterol and oxysterols) and potentially other unknown mechanisms. The immunomodulation of immune populations affects the tissue microenvironment and ultimately organ physiology, resulting in progression or resolution of pathologies such as atherosclerotic plaques.