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Liver X receptor

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LXRα (nuclear receptor subfamily 1, group H, member 3)
LXRα-RXRβ heterodimeric structure (PDB 1UHL).
Identifiers
SymbolNR1H3
NCBI gene10062
HGNC7966
OMIM602423
RefSeqNM_005693
UniProtQ13133
Search for
StructuresSwiss-model
DomainsInterPro
LXRβ (nuclear receptor subfamily 1, group H, member 2)
Identifiers
SymbolNR1H2
Alt. symbolsUNR
NCBI gene7376
HGNC7965
OMIM600380
RefSeqNM_007121
UniProtP55055
Search for
StructuresSwiss-model
DomainsInterPro

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

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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

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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

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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

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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

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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

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

Cardiovascular

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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

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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

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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

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  16. ^ Herath KB, Jayasuriya H, Guan Z, Schulman M, Ruby C, Sharma N, MacNaul K, Menke JG, Kodali S, Galgoci A, Wang J, Singh SB (September 2005). "Anthrabenzoxocinones from Streptomyces sp. as liver X receptor ligands and antibacterial agents". J. Nat. Prod. 68 (9): 1437–40. doi:10.1021/np050176k. PMID 16180833.
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  19. ^ Yoshikawa T, Shimano H, Amemiya-Kudo M, Yahagi N, Hasty AH, Matsuzaka T, Okazaki H, Tamura Y, Iizuka Y, Ohashi K, Osuga J, Harada K, Gotoda T, Kimura S, Ishibashi S, Yamada N (May 2001). "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. doi:10.1128/MCB.21.9.2991-3000.2001. PMC 86928. PMID 11287605.
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  21. ^ Wang L, Schuster GU, Hultenby K, Zhang Q, Andersson S, Gustafsson JA (October 2002). "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. Bibcode:2002PNAS...9913878W. doi:10.1073/pnas.172510899. PMC 129791. PMID 12368482.
  22. ^ Andersson S, Gustafsson N, Warner M, Gustafsson JA (March 2005). "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. Bibcode:2005PNAS..102.3857A. doi:10.1073/pnas.0500634102. PMC 553330. PMID 15738425.
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  25. ^ Joseph SB, McKilligin E, Pei L, Watson MA, Collins AR, Laffitte BA, Chen M, Noh G, Goodman J, Hagger GN, Tran J, Tippin TK, Wang X, Lusis AJ, Hsueh WA, Law RE, Collins JL, Willson TM, Tontonoz P (May 2002). "Synthetic LXR ligand inhibits the development of atherosclerosis in mice". Proc. Natl. Acad. Sci. U.S.A. 99 (11): 7604–9. Bibcode:2002PNAS...99.7604J. doi:10.1073/pnas.112059299. PMC 124297. PMID 12032330.
  26. ^ 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. PMID 11182136. S2CID 11199331.
  27. ^ a b Kratzer A, Buchebner M, Pfeifer T, Becker TM, Uray G, Miyazaki M, Miyazaki-Anzai S, Ebner B, Chandak PG, Kadam RS, Calayir E, Rathke N, Ahammer H, Radovic B, Trauner M, Hoefler G, Kompella UB, Fauler G, Levi M, Levak-Frank S, Kostner GM, Kratky D (February 2009). "Synthetic LXR agonist attenuates plaque formation in apoE-/- mice without inducing liver steatosis and hypertriglyceridemia". J. Lipid Res. 50 (2): 312–26. doi:10.1194/jlr.M800376-JLR200. PMC 2636920. PMID 18812595.
  28. ^ Laffitte BA, Chao LC, Li J, Walczak R, Hummasti S, Joseph SB, Castrillo A, Wilpitz DC, Mangelsdorf DJ, Collins JL, Saez E, Tontonoz P (April 2003). "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. Bibcode:2003PNAS..100.5419L. doi:10.1073/pnas.0830671100. PMC 154360. PMID 12697904.
  29. ^ 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. PMID 12524534. S2CID 10356659.
  30. ^ a b Anderson A, Campo A, Fulton E, Corwin A, Jerome WG 3rd, O'Connor MS (2020). "7-Ketocholesterol in disease and aging". Redox Biology. 29: 101380. doi:10.1016/j.redox.2019.101380. PMC 6926354. 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. PMC 2687050. PMID 18240340.
  32. ^ Im SS, Osborne TF (April 2011). "Liver x receptors in atherosclerosis and inflammation". Circulation Research. 108 (8): 996–1001. doi:10.1161/CIRCRESAHA.110.226878. PMC 3082200. PMID 21493922.
  33. ^ Koldamova RP, Lefterov IM, Staufenbiel M, Wolfe D, Huang S, Glorioso JC, Walter M, Roth MG, Lazo JS (February 2005). "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. doi:10.1074/jbc.M411420200. PMID 15557325.
  34. ^ Fukuchi J, Kokontis JM, Hiipakka RA, Chuu CP, Liao S (November 2004). "Antiproliferative effect of liver X receptor agonists on LNCaP human prostate cancer cells". Cancer Res. 64 (21): 7686–9. doi:10.1158/0008-5472.CAN-04-2332. PMID 15520170.
  35. ^ Chuu CP, Hiipakka RA, Kokontis JM, Fukuchi J, Chen RY, Liao S (July 2006). "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. doi:10.1158/0008-5472.CAN-06-0632. PMID 16818617.
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