Two isoforms of LXR have been identified and are referred to as LXRα and LXRβ. The liver X receptors are classified into subfamily 1 (thyroid hormone receptor-like) of the nuclear receptor superfamily, and are given the nuclear receptor nomenclature symbols NR1H3 (LXRα) and NR1H2 (LXRβ) respectively.
LXRα and LXRβ were discovered separately between 1994-1995. LXRα isoform was independently identified by two groups and initially named RLD-1 and LXR, whereas four groups identified the LXRβ isoform and called it UR, NER, OR-1, and RIP-15. The human LXRα gene is located on chromosome 11p11.2, while the LXRβ gene is located on chromosome 19q13.3.
While the expression of LXRα and LXRβ in various tissues somewhat overlap, the tissue distribution pattern of these two isoforms overall differ considerably. LXRα expression is restricted to liver, kidney, intestine, fat tissue, macrophages, lung, and spleen and is highest in liver, hence the name liver X receptor α (LXRα). LXRβ is expressed in almost all tissues and organs, hence the early name UR (ubiquitous receptor). The different pattern of expression suggests that LXRα and LXRβ have different roles in regulating physiological function.
LXRα and LXRβ form heterodimers with the obligate partner 9-cis retinoic acid receptor (RXR). The LXR/RXR heterodimer can be activated with either an LXR agonist (oxysterols) or a RXR agonist (9-cis-retinoic acid). Oxysterols, the oxygenated derivatives of cholesterol, such as 22(R)-hydroxycholesterol,24(S)-hydroxycholesterol, 27-hydroxycholesterol, and cholestenoic acid, are the natural ligands for LXR. After activation, LXR translocates to the nucleus and binds to LXR response element (LXRE), usually a variant of the idealized sequence AGGTCAN4AGGTCA, in the promoters of LXRs' target genes. Some synthetic LXR agonists have been developed, including nonsteroidal LXR agonists T0901317 and GW3965.
The importance of LXRs in physiological lipid and cholesterolmetabolism suggests that they may influence the development of metabolic disorders such as hyper lipidemia and atherosclerosis. Evidence for this idea has been observed by recent studies that linked LXR activity to the pathogenesis of atherosclerosis. LXRα knockout mice are healthy when fed with a low-cholesterol diet. However, LXRα knockout mice develop enlarged fatty livers, degeneration of liver cells, high cholesterol levels in liver, and impaired liver function when fed a high-cholesterol diet. LXRβ knockout mice are unaffected by a high-cholesterol diet, suggesting that LXRα and LXRβ have separate roles. LXRs regulate fatty acid synthesis by modulating the expression of sterol regulatory element binding protein-1c (SREBP-1c). LXRs also regulate lipidhomeostasis in the brain. LXRα and LXRβ double knockout mice develop neurodegenerative changes in brain tissue. LXRβ knockout mice results in adult-onset motor neuron degeneration in male mice.
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