Theliver X receptor (LXR) is a member of thenuclear receptor family oftranscription factors and is closely related to nuclear receptors such as thePPARs,FXR andRXR. Liver X receptors (LXRs) are important regulators ofcholesterol,fatty acid, andglucosehomeostasis. LXRs were earlier classified asorphan nuclear receptors, however, upon discovery of endogenousoxysterols as ligands they were subsequently deorphanized.
Twoisoforms of LXR have been identified and are referred to asLXRα andLXRβ. The liver X receptors are classified into subfamily 1 (thyroid hormone receptor-like) of thenuclear 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[1] and LXR,[2] whereas four groups identified the LXRβ isoform and called it UR,[3] NER,[4] OR-1,[5] and RIP-15.[6] The human LXRαgene is located onchromosome 11p11.2, while the LXRβgene is located onchromosome 19q13.3.
While the expression of LXRα and LXRβ in varioustissues overlap the tissue distribution pattern of these two isoforms differ considerably. LXRα expression is restricted toliver,kidney,intestine,fat tissue,macrophages,lung, andspleen and is highest inliver, hence the name liver X receptor α (LXRα). LXRβ is expressed in almost alltissues andorgans hence the early name UR (ubiquitous receptor).[7] The different pattern of expression suggests that LXRα and LXRβ have different roles in regulating physiological function.
Crystal structure of human liver X receptor β (LXRβ) forms a heterodimer with its partner retinoid X receptor α (RXRα) on its cognate element an AGGTCA direct repeat spaced by 4 nucleotides showing an extended X-shaped arrangement with DNA- and ligand-binding domains crossed. In contrast, the parallel domain arrangement of other NRs bind an AGGTCA direct repeat spaced by 1 nucleotide. The LXRβ core binds DNA via canonical contacts and auxiliary DNA contacts that enhance affinity for the response element.[8]
LXRα-RXRβ active site with T-0901317 bound (PDB 1UHL).
Crystal structure of human liver X receptor α (LXRα) also forms a heterodimer with its partner retinoid X receptor β (RXRβ). The LXRα-RXRβ heterodimer (PDB 1UHL) binds synthetic LXR oxysterol agonist T-0901317. The ligand-binding pocket predominantly consists of hydrophobic residues. The most critical residues to the binding pocket include E267, R305, H421, and W443. The binding pocket accommodates oxysterols of molecular volumes up to 400 Å3 and T-0901317 easily positions itself with a molecular volume of 304 Å3. H421 forms a hydrogen bond with T-0901317's hydroxyl head group which lowers the pKa of the H421 imidazole side chain. As a result, the imidazole side chain interacts electrostatically with π-electrons of W443's indole side chain to stabilize the active conformation of the helices.[9]
The phenyl group of T-0901317 extends toward the β-sheet side of the binding pocket and partially occupies it. The unoccupied section contains hydrophilic, polar residues E267 and R305. H421 and W443 anchor the 22-, 24-, or 27-hydroxyl group of an oxysterol to the binding pocket via hydrogen bonding and electrostatic interactions. The conformational flexibility of R305 allows it to bind the 3-hydroxyl group and stabilize an oxysterol.[9]
The hexacyclic aromatic ketones, (-)anthrabenzoxocinone and (-)bischloroanthrabenzoxocinone ((-)-BABX) derived from aStreptomyces sp. have micromolar affinity for LXR-α.[16]
LXR-RXR nuclear receptor heterodimers function as transcriptional regulators for genes involved in lipid metabolism, lipid homeostasis, and inflammation.[9] Targetgenes of LXRs are involved incholesterol andlipidmetabolism regulation,[17] including:
Aberrant LXR signaling inmacrophages due to theoxidizedcholesterol 7-ketocholesterol promotes the inflammation that leads toatherosclerosis.[30] For this reason, 7-ketocholesterol is a therapeutic target for the prevention and treatment of atherosclerosis.[30]
When lipogenesis is increased by pharmacological activation of the liver X receptor, hepatic VLDL production is increased 2.5-fold, and the liver produces large TG-rich VLDL particles. Glucose induces expression of LXR target genes involved in cholesterol homeostasis likeABCA1 which is defective inTangier disease. A common feature of many metabolic pathways is their control byretinoid X receptor (RXR) heterodimers. LXR heterodimerises with RXR. Promiscuous RXR also heterodimerises with PPAR members.PPAR-α plays a pivotal role in fatty acid catabolism in liver by upregulating the expression of numerous genes involved in mitochondrial fatty acid oxidation. Thus RXR is a common partner of two nuclear receptors acting in opposite directions with regard to fatty acid metabolism. So both LXR and PPAR-α compete for the limited pool of RXR and this dynamic equilibrium determines the direction of lipid metabolism.[31]
Developing new potent and effective LXRagonists without the undesirable side effects may be beneficial for clinical usage.[32] In this regard, DMHCA was reported to reduce atherosclerosis in apolipoprotein E-deficient mice without inducing hypertriglyceridemia and liver steatosis.[27]
Treatment with T0901317 decreases amyloidal beta production in anAlzheimer's disease mouse model.[33] However, both T0901317 and GW3965 have been reported to increaseplasma andlivertriglycerides in some mice models, indicating that T0901317 and GW3965 may not be a good candidate for a therapeutic agent.
LXR agonists (T0901317, 22(R)-hydroxycholesterol, and 24(S)-hydroxycholesterol) were also shown to suppress the proliferation ofprostate cancer andbreast cancer cells[34] as well as delay progression ofprostate cancer fromandrogen-dependent status toandrogen-independent status.[35]
^Shinar DM, Endo N, Rutledge SJ, Vogel R, Rodan GA, Schmidt A (September 1994). "NER, a new member of the gene family encoding the human steroid hormone nuclear receptor".Gene.147 (2):273–6.doi:10.1016/0378-1119(94)90080-9.PMID7926814.
^Chuu CP, Kokontis JM, Hiipakka RA, Liao S (September 2007). "Modulation of liver X receptor signaling as novel therapy for prostate cancer".J. Biomed. Sci.14 (5):543–53.doi:10.1007/s11373-007-9160-8.PMID17372849.
^Lou X, Toresson G, Benod C, Suh JH, Philips KJ, Webb P, Gustafsson JA (March 2014). "Structure of the retinoid X receptor α-liver X receptor β (RXRα-LXRβ) heterodimer on DNA".Nature Structural & Molecular Biology.21 (3):277–81.doi:10.1038/nsmb.2778.PMID24561505.S2CID23226682.
^abcHoerer S, Schmid A, Heckel A, Budzinski RM, Nar H (December 2003). "Crystal structure of the human liver X receptor beta ligand-binding domain in complex with a synthetic agonist".Journal of Molecular Biology.334 (5):853–61.doi:10.1016/j.jmb.2003.10.033.PMID14643652.S2CID43844694.
^Song C, Hiipakka RA, Liao S (June 2001). "Auto-oxidized cholesterol sulfates are antagonistic ligands of liver X receptors: implications for the development and treatment of atherosclerosis".Steroids.66 (6):473–9.doi:10.1016/S0039-128X(00)00239-7.PMID11182136.S2CID11199331.
^Joseph SB, Castrillo A, Laffitte BA, Mangelsdorf DJ, Tontonoz P (February 2003). "Reciprocal regulation of inflammation and lipid metabolism by liver X receptors".Nat. Med.9 (2):213–9.doi:10.1038/nm820.PMID12524534.S2CID10356659.
