LXRα (nuclear receptor subfamily 1, group H, member 3) | |||||||
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Identifiers | |||||||
Symbol | NR1H3 | ||||||
NCBI gene | 10062 | ||||||
HGNC | 7966 | ||||||
OMIM | 602423 | ||||||
RefSeq | NM_005693 | ||||||
UniProt | Q13133 | ||||||
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LXRβ (nuclear receptor subfamily 1, group H, member 2) | |||||||
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Identifiers | |||||||
Symbol | NR1H2 | ||||||
Alt. symbols | UNR | ||||||
NCBI gene | 7376 | ||||||
HGNC | 7965 | ||||||
OMIM | 600380 | ||||||
RefSeq | NM_007121 | ||||||
UniProt | P55055 | ||||||
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The liver X receptor (LXR) is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXRs were earlier classified as orphan nuclear receptors, however, upon discovery of endogenous oxysterols as ligands they were subsequently deorphanized.
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 [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 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 overlap the tissue distribution pattern of these two isoforms 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). [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]
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]
LXRα and LXRβ form heterodimers with the obligate partner retinoid X receptor (RXR), which is activated by 9-cis-13,14-dihydroretinoic acid. [10] The LXR/RXR heterodimer can be activated with either an LXR agonist (oxysterols) or a RXR agonist (9-cis-13,14-dihydroretinoic 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. [11] [12] [13] [14] After activation, LXR 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 [15] and GW3965.
The hexacyclic aromatic ketones, (-)anthrabenzoxocinone and (-)bischloroanthrabenzoxocinone ((-)-BABX) derived from a Streptomyces sp. have micromolar affinity for LXR-α. [16]
LXR-623 (WAY 252623) CAS: [875787-07-8].
LXR-RXR nuclear receptor heterodimers function as transcriptional regulators for genes involved in lipid metabolism, lipid homeostasis, and inflammation. [9] Target genes of LXRs are involved in cholesterol and lipid metabolism regulation, [17] including:
The importance of LXRs in physiological lipid and cholesterol metabolism suggests that they may influence the development of metabolic disorders such as hyperlipidemia 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. [18] 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). [19] [20] LXRs also regulate lipid homeostasis in the brain. LXRα and LXRβ double knockout mice develop neurodegenerative changes in brain tissue. [21] LXRβ knockout mice results in adult-onset motor neuron degeneration in male mice. [22]
Adiponectin induces ABCA1-mediated reverse cholesterol transport by activation of PPAR-γ and LXRα/β. [23]
LXR agonists are effective for treatment of murine models of atherosclerosis, diabetes, anti-inflammation, Alzheimer's disease, and cancer.
Treatment with LXR agonists (hypocholamide, T0901317, GW3965, or N,N-dimethyl-3beta-hydroxy-cholenamide (DMHCA)) lowers the cholesterol level in serum and liver and inhibits the development of atherosclerosis in murine disease models. [24] [25] [26] [27] Synthetic LXR agonist GW3965 improves glucose tolerance in a murine model of diet-induced obesity and insulin resistance by regulating genes involved in glucose metabolism in liver and adipose tissue. [28] GW3965 inhibits the expression of inflammatory mediators in cultured macrophage and inflammation in mice. [29]
Aberrant LXR signaling in macrophages due to the oxidized cholesterol 7-ketocholesterol promotes the inflammation that leads to atherosclerosis. [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 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-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 LXR agonists 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 an Alzheimer's disease mouse model. [33] However, both T0901317 and GW3965 have been reported to increase plasma and liver triglycerides 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 of prostate cancer and breast cancer cells [34] as well as delay progression of prostate cancer from androgen-dependent status to androgen-independent status. [35]
In the field of molecular biology, the peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism, and tumorigenesis of higher organisms.
The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone. TRs act as transcription factors, ultimately affecting the regulation of gene transcription and translation. These receptors also have non-genomic effects that lead to second messenger activation, and corresponding cellular response.
The retinoic acid receptor (RAR) is a type of nuclear receptor which can also act as a ligand-activated transcription factor that is activated by both all-trans retinoic acid and 9-cis retinoic acid, retinoid active derivatives of Vitamin A. They are typically found within the nucleus. There are three retinoic acid receptors (RAR), RAR-alpha, RAR-beta, and RAR-gamma, encoded by the RARA, RARB, RARG genes, respectively. Within each RAR subtype there are various isoforms differing in their N-terminal region A. Multiple splice variants have been identified in human RARs: four for RARA, five for RARB, and two for RARG. As with other type II nuclear receptors, RAR heterodimerizes with RXR and in the absence of ligand, the RAR/RXR dimer binds to hormone response elements known as retinoic acid response elements (RAREs) complexed with corepressor protein. Binding of agonist ligands to RAR results in dissociation of corepressor and recruitment of coactivator protein that, in turn, promotes transcription of the downstream target gene into mRNA and eventually protein. In addition, the expression of RAR genes is under epigenetic regulation by promoter methylation. Both the length and magnitude of the retinoid response is dependent of the degradation of RARs and RXRs through the ubiquitin-proteasome. This degradation can lead to elongation of the DNA transcription through disruption of the initiation complex or to end the response to facilitate further transcriptional programs. Due to RAR/RXR heterodimers acting as subtrates to the non steroid hormone ligand retinoid they are extensively involved in cell differentiation, proliferation, and apoptosis.
The retinoid X receptor (RXR) is a type of nuclear receptor that is activated by 9-cis retinoic acid, which is discussed controversially to be of endogenous relevance, and 9-cis-13,14-dihydroretinoic acid, which is likely to be the major endogenous mammalian RXR-selective agonist.
The bile acid receptor (BAR), also known as farnesoid X receptor (FXR) or NR1H4, is a nuclear receptor that is encoded by the NR1H4 gene in humans.
In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These intracellular receptors work with other proteins to regulate the expression of specific genes thereby controlling the development, homeostasis, and metabolism of the organism.
Cholesterol 7 alpha-hydroxylase also known as cholesterol 7-alpha-monooxygenase or cytochrome P450 7A1 (CYP7A1) is an enzyme that in humans is encoded by the CYP7A1 gene which has an important role in cholesterol metabolism. It is a cytochrome P450 enzyme, which belongs to the oxidoreductase class, and converts cholesterol to 7-alpha-hydroxycholesterol, the first and rate limiting step in bile acid synthesis.
The RAR-related orphan receptors (RORs) are members of the nuclear receptor family of intracellular transcription factors. There are three forms of ROR, ROR-α, -β, and -γ and each is encoded by a separate gene, RORA, RORB, and RORC respectively. The RORs are somewhat unusual in that they appear to bind as monomers to hormone response elements as opposed to the majority of other nuclear receptors which bind as dimers. They bind to DNA elements called ROR response elements (RORE).
The small heterodimer partner (SHP) also known as NR0B2 is a protein that in humans is encoded by the NR0B2 gene. SHP is a member of the nuclear receptor family of intracellular transcription factors. SHP is unusual for a nuclear receptor in that it lacks a DNA binding domain. Therefore, it is technically neither a transcription factor nor nuclear receptor but nevertheless it is still classified as such due to relatively high sequence homology with other nuclear receptor family members.
Peroxisome proliferator- activated receptor gamma, also known as the glitazone reverse insulin resistance receptor, or NR1C3 is a type II nuclear receptor functioning as a transcription factor that in humans is encoded by the PPARG gene.
RAR-related orphan receptor alpha (RORα), also known as NR1F1 is a nuclear receptor that in humans is encoded by the RORA gene. RORα participates in the transcriptional regulation of some genes involved in circadian rhythm. In mice, RORα is essential for development of cerebellum through direct regulation of genes expressed in Purkinje cells. It also plays an essential role in the development of type 2 innate lymphoid cells (ILC2) and mutant animals are ILC2 deficient. In addition, although present in normal numbers, the ILC3 and Th17 cells from RORα deficient mice are defective for cytokine production.
Retinoid X receptor alpha (RXR-alpha), also known as NR2B1 is a nuclear receptor that in humans is encoded by the RXRA gene.
Peroxisome proliferator-activated receptor alpha (PPAR-α), also known as NR1C1, is a nuclear receptor protein functioning as a transcription factor that in humans is encoded by the PPARA gene. Together with peroxisome proliferator-activated receptor delta and peroxisome proliferator-activated receptor gamma, PPAR-alpha is part of the subfamily of peroxisome proliferator-activated receptors. It was the first member of the PPAR family to be cloned in 1990 by Stephen Green and has been identified as the nuclear receptor for a diverse class of rodent hepatocarcinogens that causes proliferation of peroxisomes.
Liver X receptor alpha (LXR-alpha) is a nuclear receptor protein that in humans is encoded by the NR1H3 gene.
Retinoid X receptor beta (RXR-beta), also known as NR2B2 is a nuclear receptor that in humans is encoded by the RXRB gene.
Peroxisome proliferator-activated receptor delta(PPAR-delta), or (PPAR-beta), also known as Nuclear hormone receptor 1(NUC1) is a nuclear receptor that in humans is encoded by the PPARD gene.
Retinoic acid receptor gamma (RAR-γ), also known as NR1B3 is a nuclear receptor encoded by the RARG gene. Adapalene selectively targets retinoic acid receptor beta and retinoic acid receptor gamma and its agonism of the gamma subtype is largely responsible for adapalene's observed effects.
Liver X receptor beta (LXR-β) is a member of the nuclear receptor family of transcription factors. LXR-β is encoded by the NR1H2 gene.
Insulin induced gene 2, also known as INSIG2, is a protein which in humans is encoded by the INSIG2 gene.
24S-Hydroxycholesterol (24S-HC), also known as cholest-5-ene-3,24-diol or cerebrosterol, is an endogenous oxysterol produced by neurons in the brain to maintain cholesterol homeostasis. It was discovered in 1953 by Alberto Ercoli, S. Di Frisco, and Pietro de Ruggieri, who first isolated the molecule in the horse brain and then demonstrated its presence in the human brain.