LXRs

LXRs, or Liver X Receptors, are a family of nuclear hormone receptors that regulate cholesterol and lipid metabolism and modulate inflammatory responses. There are two isoforms: LXR alpha (NR1H3) and LXR beta (NR1H2). LXRα is highly expressed in liver, intestine, adipose tissue, and macrophages, whereas LXRβ is expressed more broadly across tissues. Both isoforms function as transcription factors that form heterodimers with retinoid X receptors (RXR) and bind to LXR response elements in target gene promoters.

Endogenous and synthetic ligands activate LXRs. Natural ligands include oxysterols such as 24(S)-hydroxycholesterol and 27-hydroxycholesterol. Synthetic agonists, such as T0901317 and GW3965, have been used in research to study LXR functions, though their use can have off-target effects.

Functions of LXRs include regulation of cholesterol homeostasis, lipid metabolism, and inflammatory responses. Activation promotes cholesterol efflux from cells by upregulating transporters like ABCA1 and ABCG1, supporting reverse cholesterol transport. LXRs also influence the expression of apolipoproteins such as ApoA1 and ApoE. In lipid metabolism, LXR activation can induce the lipogenic transcription factor SREBP-1c and downstream enzymes, potentially increasing fatty acid synthesis and contributing to hepatic steatosis if overstimulated. In immune cells, LXRs exert anti-inflammatory effects by dampening NF-kB signaling and cytokine production.

Clinical and research relevance centers on LXRs as potential targets for atherosclerosis and metabolic syndrome. Therapeutic strategies aim for tissue-selective or modulated activation to balance cholesterol handling with minimized lipogenesis. Genetic and pharmacological studies in animals have highlighted distinct, overlapping roles for LXRα and LXRβ in different tissues.