Biology:Liver X receptor

From HandWiki
Short description: Nuclear receptor
LXRα (nuclear receptor subfamily 1, group H, member 3)
LXRα-RXR whole structure.png
LXRα-RXRβ heterodimeric structure (PDB 1UHL).
Identifiers
SymbolNR1H3
NCBI gene10062
HGNC7966
OMIM602423
RefSeqNM_005693
UniProtQ13133
LXRβ (nuclear receptor subfamily 1, group H, member 2)
Identifiers
SymbolNR1H2
Alt. symbolsUNR
NCBI gene7376
HGNC7965
OMIM600380
RefSeqNM_007121
UniProtP55055

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.

Expression

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.

Structure

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]

Activation/ligands

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].

Target genes

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:

  • 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 7α-hydroxylase
  • LPL – LipoProtein Lipase
  • LXR-α – Liver X Receptor-α (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. 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]

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.[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]

Alzheimer's disease

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.

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[34] as well as delay progression of prostate cancer from androgen-dependent status to androgen-independent status.[35]

References

  1. ↑ "A novel orphan receptor specific for a subset of thyroid hormone-responsive elements and its interaction with the retinoid/thyroid hormone receptor subfamily". Mol. Cell. Biol. 14 (10): 7025–35. October 1994. doi:10.1128/mcb.14.10.7025. PMID 7935418. 
  2. ↑ "LXR, a nuclear receptor that defines a distinct retinoid response pathway". Genes Dev. 9 (9): 1033–45. May 1995. doi:10.1101/gad.9.9.1033. PMID 7744246. 
  3. ↑ "Ubiquitous receptor: a receptor that modulates gene activation by retinoic acid and thyroid hormone receptors". Proc. Natl. Acad. Sci. U.S.A. 91 (23): 10809–13. November 1994. doi:10.1073/pnas.91.23.10809. PMID 7971966. Bibcode: 1994PNAS...9110809S. 
  4. ↑ "NER, a new member of the gene family encoding the human steroid hormone nuclear receptor". Gene 147 (2): 273–6. September 1994. doi:10.1016/0378-1119(94)90080-9. PMID 7926814. 
  5. ↑ "OR-1, a member of the nuclear receptor superfamily that interacts with the 9-cis-retinoic acid receptor". Proc. Natl. Acad. Sci. U.S.A. 92 (6): 2096–100. March 1995. doi:10.1073/pnas.92.6.2096. PMID 7892230. Bibcode: 1995PNAS...92.2096T. 
  6. ↑ "Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors". Mol. Endocrinol. 9 (1): 72–85. January 1995. doi:10.1210/mend.9.1.7760852. PMID 7760852. 
  7. ↑ "Modulation of liver X receptor signaling as novel therapy for prostate cancer". J. Biomed. Sci. 14 (5): 543–53. September 2007. doi:10.1007/s11373-007-9160-8. PMID 17372849. 
  8. ↑ "Structure of the retinoid X receptor α-liver X receptor β (RXRα-LXRβ) heterodimer on DNA". Nature Structural & Molecular Biology 21 (3): 277–81. March 2014. doi:10.1038/nsmb.2778. PMID 24561505. 
  9. ↑ 9.0 9.1 9.2 "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. December 2003. doi:10.1016/j.jmb.2003.10.033. PMID 14643652. 
  10. ↑ "9-cis-13,14-Dihydroretinoic Acid Is an Endogenous Retinoid Acting as RXR Ligand in Mice". PLOS Genetics 11 (6): e1005213. June 2015. doi:10.1371/journal.pgen.1005213. PMID 26030625. 
  11. ↑ "An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha". Nature 383 (6602): 728–31. October 1996. doi:10.1038/383728a0. PMID 8878485. Bibcode: 1996Natur.383..728J. 
  12. ↑ "The orphan nuclear receptor LXRα is positively and negatively regulated by distinct products of mevalonate metabolism". Proc. Natl. Acad. Sci. U.S.A. 94 (20): 10588–93. September 1997. doi:10.1073/pnas.94.20.10588. PMID 9380679. Bibcode: 1997PNAS...9410588F. 
  13. ↑ "Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway". J. Biol. Chem. 272 (6): 3137–40. February 1997. doi:10.1074/jbc.272.6.3137. PMID 9013544. 
  14. ↑ "Cholestenoic acid is a naturally occurring ligand for liver X receptor alpha". Endocrinology 141 (11): 4180–4. November 2000. doi:10.1210/endo.141.11.7772. PMID 11089551. 
  15. ↑ "Role of LXRs in control of lipogenesis". Genes Dev. 14 (22): 2831–8. November 2000. doi:10.1101/gad.850400. PMID 11090131. 
  16. ↑ "Anthrabenzoxocinones from Streptomyces sp. as liver X receptor ligands and antibacterial agents". J. Nat. Prod. 68 (9): 1437–40. September 2005. doi:10.1021/np050176k. PMID 16180833. 
  17. ↑ "LXRs; oxysterol-activated nuclear receptors that regulate genes controlling lipid homeostasis". Vascul. Pharmacol. 38 (4): 249–56. April 2002. doi:10.1016/S1537-1891(02)00175-1. PMID 12449021. 
  18. ↑ "Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha". Cell 93 (5): 693–704. May 1998. doi:10.1016/S0092-8674(00)81432-4. PMID 9630215. 
  19. ↑ "Identification of Liver X Receptor-Retinoid X Receptor as an Activator of the Sterol Regulatory Element-Binding Protein 1c Gene Promoter". Mol. Cell. Biol. 21 (9): 2991–3000. May 2001. doi:10.1128/MCB.21.9.2991-3000.2001. PMID 11287605. 
  20. ↑ "Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ". Genes Dev. 14 (22): 2819–30. November 2000. doi:10.1101/gad.844900. PMID 11090130. 
  21. ↑ "Liver X receptors in the central nervous system: From lipid homeostasis to neuronal degeneration". Proc. Natl. Acad. Sci. U.S.A. 99 (21): 13878–83. October 2002. doi:10.1073/pnas.172510899. PMID 12368482. Bibcode: 2002PNAS...9913878W. 
  22. ↑ "Inactivation of liver X receptor β leads to adult-onset motor neuron degeneration in male mice". Proc. Natl. Acad. Sci. U.S.A. 102 (10): 3857–62. March 2005. doi:10.1073/pnas.0500634102. PMID 15738425. Bibcode: 2005PNAS..102.3857A. 
  23. ↑ "The role of adiponectin in cholesterol efflux and HDL biogenesis and metabolism". Metabolism 100: 153953. 2019. doi:10.1016/j.metabol.2019.153953. PMID 31377319. 
  24. ↑ "Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRβ-deficient mice". J. Clin. Invest. 107 (5): 565–73. March 2001. doi:10.1172/JCI9794. PMID 11238557. 
  25. ↑ "Synthetic LXR ligand inhibits the development of atherosclerosis in mice". Proc. Natl. Acad. Sci. U.S.A. 99 (11): 7604–9. May 2002. doi:10.1073/pnas.112059299. PMID 12032330. Bibcode: 2002PNAS...99.7604J. 
  26. ↑ "Auto-oxidized cholesterol sulfates are antagonistic ligands of liver X receptors: implications for the development and treatment of atherosclerosis". Steroids 66 (6): 473–9. June 2001. doi:10.1016/S0039-128X(00)00239-7. PMID 11182136. 
  27. ↑ 27.0 27.1 "Synthetic LXR agonist attenuates plaque formation in apoE-/- mice without inducing liver steatosis and hypertriglyceridemia". J. Lipid Res. 50 (2): 312–26. February 2009. doi:10.1194/jlr.M800376-JLR200. PMID 18812595. 
  28. ↑ "Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue". Proc. Natl. Acad. Sci. U.S.A. 100 (9): 5419–24. April 2003. doi:10.1073/pnas.0830671100. PMID 12697904. Bibcode: 2003PNAS..100.5419L. 
  29. ↑ "Reciprocal regulation of inflammation and lipid metabolism by liver X receptors". Nat. Med. 9 (2): 213–9. February 2003. doi:10.1038/nm820. PMID 12524534. 
  30. ↑ 30.0 30.1 "7-Ketocholesterol in disease and aging". Redox Biology 29: 101380. 2020. doi:10.1016/j.redox.2019.101380. PMID 31926618. 
  31. ↑ Sanal MG (2008). "The blind men 'see' the elephant-the many faces of fatty liver disease". World J. Gastroenterol. 14 (6): 831–44. doi:10.3748/wjg.14.831. PMID 18240340. 
  32. ↑ "Liver x receptors in atherosclerosis and inflammation". Circulation Research 108 (8): 996–1001. April 2011. doi:10.1161/CIRCRESAHA.110.226878. PMID 21493922. 
  33. ↑ "The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer's disease". J. Biol. Chem. 280 (6): 4079–88. February 2005. doi:10.1074/jbc.M411420200. PMID 15557325. 
  34. ↑ "Antiproliferative effect of liver X receptor agonists on LNCaP human prostate cancer cells". Cancer Res. 64 (21): 7686–9. November 2004. doi:10.1158/0008-5472.CAN-04-2332. PMID 15520170. 
  35. ↑ "Inhibition of tumor growth and progression of LNCaP prostate cancer cells in athymic mice by androgen and liver X receptor agonist". Cancer Res. 66 (13): 6482–6. July 2006. doi:10.1158/0008-5472.CAN-06-0632. PMID 16818617. 

External links



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:Liver_X_receptor&oldid=3598246"