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Two isoforms of LXR have been identified and are referred to as LXR? and LXR?. 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 (LXR?) and NR1H2 (LXR?) respectively.
LXR? and LXR? were discovered separately between 1994-1995. LXR? isoform was independently identified by two groups and initially named RLD-1 and LXR, whereas four groups identified the LXR? isoform and called it UR, NER, OR-1, and RIP-15. The human LXR? gene is located on chromosome 11p11.2, while the LXR? gene is located on chromosome 19q13.3.
While the expression of LXR? and LXR? in various tissues overlap the tissue distribution pattern of these two isoforms differ considerably. LXR? expression is restricted to liver, kidney, intestine, fat tissue, macrophages, lung, and spleen and is highest in liver, hence the name liver X receptor ? (LXR?). LXR? is expressed in almost all tissues and organs hence the early name UR (ubiquitous receptor). The different pattern of expression suggests that LXR? and LXR? have different roles in regulating physiological function.
Crystal structure of human liver X receptor ? (LXR?) forms a heterodimer with its partner retinoid X receptor ? (RXR?) 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 LXR? core binds DNA via canonical contacts and auxiliary DNA contacts that enhance affinity for the response element.
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 like ABCA1 which is defective in Tangier disease. A common feature of many metabolic pathways is their control by retinoid X receptor (RXR) heterodimers. LXR heterodimerises with RXR. Promiscuous RXR also heterodimerises with PPAR members. PPAR-? 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-? compete for the limited pool of RXR and this dynamic equilibrium determines the direction of lipid metabolism.
Developing new potent and effective LXR agonists without the undesirable side effects may be beneficial for clinical usage. In this regard, DMHCA was reported to reduce atherosclerosis in apolipoprotein E-deficient mice without inducing hypertriglyceridemia and liver steatosis.
Treatment with T0901317 decreases amyloidal beta production in an Alzheimer's disease mouse model. However, both T0901317 and GW3965 have been reported to increase plasma and livertriglycerides in some mice models, indicating that T0901317 and GW3965 may not be a good candidate for a therapeutic agent.
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