Liver X Receptor
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Liver X Receptor

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 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[1] and LXR,[2] whereas four groups identified the LXR? isoform and called it UR,[3] NER,[4] OR-1,[5] and RIP-15.[6] The human LXR? gene is located on chromosome 11p11.2, while the LXR? gene is located on chromosome 19q13.3.

Expression

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).[7] The different pattern of expression suggests that LXR? and LXR? have different roles in regulating physiological function.

Structure

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.[8]

Activation/ligands

LXR? and LXR? form heterodimers with the obligate partner retinoid X receptor (RXR), which is activated by 9-cis-13,14-dihydroretinoic acid.[9] 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.[10][11][12][13] 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[14] and GW3965.

The hexacyclic aromatic ketones, (-)anthrabenzoxocinone and (-)bischloroanthrabenzoxocinone ((-)-BABX) derived from a Streptomyces sp. have micromolar affinity for LXR-?.[15]

LXR-623 (WAY 252623) CAS: [875787-07-8].

Target genes

Target genes of LXRs are involved in cholesterol and lipid metabolism regulation,[16] including:

  • ABC - ATP Binding Cassette transporter isoforms A1, G1, G5, and G8
  • ApoE - Apolipoprotein E
  • CETP - CholEsterylester Transfer Protein
  • FAS - Fatty Acid Synthase
  • CYP7A1 - CYtochrome P450 isoform 7A1 - cholesterol 7?-hydroxylase
  • LPL - LipoProtein Lipase
  • LXR-? - Liver X Receptor-? (a somewhat unusual example of receptor up-regulating its own expression)
  • SREBP-1c - Sterol Regulatory Element Binding Protein 1c
  • ChREBP - Carbohydrate Regulatory Element Binding Protein

Role in metabolism

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. LXR? knockout mice are healthy when fed with a low-cholesterol diet. However, LXR? 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.[17] LXR? knockout mice are unaffected by a high-cholesterol diet, suggesting that LXR? and LXR? have separate roles. LXRs regulate fatty acid synthesis by modulating the expression of sterol regulatory element binding protein-1c (SREBP-1c).[18][19] LXRs also regulate lipid homeostasis in the brain. LXR? and LXR? double knockout mice develop neurodegenerative changes in brain tissue.[20] LXR? knockout mice results in adult-onset motor neuron degeneration in male mice.[21]

Adiponectin induces ABCA1-mediated reverse cholesterol transport by activation of PPAR-? and LXR?/?.[22]

Potential therapeutic applications of LXR agonists

LXR agonists are effective for treatment of murine models of atherosclerosis, diabetes, anti-inflammation, Alzheimer's disease, and cancer.

Cardiovascular

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.[23][24][25][26] 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.[27] GW3965 inhibits the expression of inflammatory mediators in cultured macrophage and inflammation in mice.[28]

Aberrant LXR signaling in macrophages due to the oxidized cholesterol 7-ketocholesterol promotes the inflammation that leads to atherosclerosis.[29] For this reason, 7-ketocholesterol is a therapeutic target for the prevention and treatment of atherosclerosis.[29]

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.[30]

Developing new potent and effective LXR agonists without the undesirable side effects may be beneficial for clinical usage.[31] In this regard, DMHCA was reported to reduce atherosclerosis in apolipoprotein E-deficient mice without inducing hypertriglyceridemia and liver steatosis.[26]

Alzheimer's disease

Treatment with T0901317 decreases amyloidal beta production in an Alzheimer's disease mouse model.[32] 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.

Cancer

LXR agonists (T0901317, 22(R)-hydroxycholesterol, and 24(S)-hydroxycholesterol) were also shown to suppress the proliferation of prostate cancer and breast cancer cells[33] as well as delay progression of prostate cancer from androgen-dependent status to androgen-independent status.[34]

References

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