Liver X receptor

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LXRα (nuclear receptor subfamily 1, group H, member 3)
Identifiers
SymbolNR1H3
Entrez10062
HUGO7966
OMIM602423
RefSeqNM_005693
UniProtQ13133
LXRβ (nuclear receptor subfamily 1, group H, member 2)
Identifiers
SymbolNR1H2
Alt. symbolsUNR
Entrez7376
HUGO7965
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 PPAR, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. Since there is no clear consensus on what the endogenous ligand of LXR is, LXR is referred to as an orphan receptor.

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 somewhat overlap, the tissue distribution pattern of these two isoforms overall 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.

Activation/ligands

LXRα and LXRβ form heterodimers with the obligate partner 9-cis retinoic acid receptor (RXR). The LXR/RXR heterodimer can be activated with either an LXR agonist (oxysterols) or a RXR agonist (9-cis-retinoic 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.[8][9][10][11] After activation, LXR translocates to the nucleus and 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[12] and GW3965.

Target Genes

Target genes of LXRs are involved in cholesterol and lipid metabolism regulation,[13] including:

Roles of LXR in metabolism

The importance of LXRs in physiological lipid and cholesterol metabolism suggests that they may influence the development of metabolic disorders such as hyper lipidemia 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.[14] 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 elementbinding protein-1c (SREBP-1c).[15][16] LXRs also regulate lipid homeostasis in the brain. LXRα and LXRβ double knockout mice develop neurodegenerative changes in brain tissue.[17] LXRβ knockout mice results in adult-onset motor neuron degeneration in male mice.[18]

Clinical significance of LXR agonists

LXR agonists are effective for treatment of murine models of atherosclerosis, diabetes, anti-inflammation, and Alzheimer's disease. Treatment with LXR agonists (hypocholamide, T0901317, or GW3965) lowers the cholesterol level in serum and liver and inhibits the development of atherosclerosis in murine disease models.[19][20][21] 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.[22] GW3965 inhibits the expression of inflammatory mediators in cultured macrophage and inflammation in mice.[23] LXR agonists (T0901317, 22(R)-hydroxycholesterol, and 24(S)-hydroxycholesterol) were also shown to suppress the proliferation of prostate cancer and breast cancer cells[24] as well as delay progression of prostate cancer from androgen-dependent status to androgen-independent status[25]. Treatment with T0901317 decreases amyloidal beta production in an Alzheimer's disease mouse model.[26] 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. Developing new potent and effective LXR agonists without the undesirable side effects may be beneficial for clinical usage.

References

  1. Apfel R, Benbrook D, Lernhardt E, Ortiz MA, Salbert G, Pfahl M. 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. 1994 Oct;14(10):7025-35. PMID 7935418
  2. Willy PJ, Umesono K, Ong ES, Evans RM, Heyman RA, Mangelsdorf DJ. LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev. 1995 May 1;9(9):1033-45. PMID 7744246
  3. Song C, Kokontis JM, Hiipakka RA, Liao S. Ubiquitous receptor: a receptor that modulates gene activation by retinoic acid and thyroid hormone receptors. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10809-13. PMID 7971966
  4. Shinar DM, Endo N, Rutledge SJ, Vogel R, Rodan GA, Schmidt A. NER, a new member of the gene family encoding the human steroid hormone nuclear receptor. Gene. 1994 Sep 30;147(2):273-6. PMID 7926814
  5. Teboul M, Enmark E, Li Q, Wikstrom AC, Pelto-Huikko M, Gustafsson JA. 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. 1995 Mar 14;92(6):2096-100. PMID 7892230
  6. Seol W, Choi HS, Moore DD. Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors. Mol Endocrinol. 1995 Jan;9(1):72-85. PMID 7760852
  7. Chuu CP, Kokontis JM, Hiipakka RA, Liao S. Modulation of liver X receptor signaling as novel therapy for prostate cancer. J Biomed Sci. 2007 Mar 20. PMID 17372849
  8. Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature. 1996 Oct 24;383(6602):728-31. PMID 8878485
  9. Forman BM, Ruan B, Chen J, Schroepfer GJ Jr, Evans RM. The orphan nuclear receptor LXRalpha is positively and negatively regulated by distinct products of mevalonate metabolism. Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10588-93. PMID 9380679
  10. Lehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su JL, Sundseth SS, Winegar DA, Blanchard DE, Spencer TA, Willson TM. Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem. 1997 Feb 7;272(6):3137-40. PMID 9013544
  11. Song C, Liao S. Cholestenoic acid is a naturally occurring ligand for liver X receptor alpha. Endocrinology. 2000 Nov;141(11):4180-4. PMID 11089551
  12. Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M, Mangelsdorf DJ, Lustig KD, Shan B. Role of LXRs in control of lipogenesis. Genes Dev. 2000 Nov 15;14(22):2831-8. PMID 11090131
  13. Edwards PA, Kennedy MA, Mak PA. LXRs; oxysterol-activated nuclear receptors that regulate genes controlling lipid homeostasis. PMID 12449021 Vascul Pharmacol. 2002 Apr;38(4):249-56.
  14. Peet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro JM, Hammer RE, Mangelsdorf DJ. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell. 1998 May 29;93(5):693-704. PMID 9630215
  15. 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. Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter. Mol Cell Biol. 2001 May;21(9):2991-3000. PMID 11287605
  16. Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, Shan B, Brown MS, Goldstein JL, Mangelsdorf DJ. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev. 2000 Nov 15;14(22):2819-30. PMID 11090130
  17. Wang L, Schuster GU, Hultenby K, Zhang Q, Andersson S, Gustafsson JA. Liver X receptors in the central nervous system: from lipid homeostasis to neuronal degeneration. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13878-83. PMID 12368482
  18. Andersson S, Gustafsson N, Warner M, Gustafsson JA. Inactivation of liver X receptor beta leads to adult-onset motor neuron degeneration in male mice. Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3857-62. PMID 15738425
  19. Alberti S, Schuster G, Parini P, Feltkamp D, Diczfalusy U, Rudling M, Angelin B, Bjorkhem I, Pettersson S, Gustafsson JA. Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRbeta-deficient mice. J Clin Invest. 2001 Mar;107(5):565-73. PMID 11238557
  20. 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. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc Natl Acad Sci U S A. 2002 May 28;99(11):7604-9. PMID 12032330
  21. Song C, Hiipakka RA, Liao S. Auto-oxidized cholesterol sulfates are antagonistic ligands of liver X receptors: implications for the development and treatment of atherosclerosis. Steroids. 2001 Jun;66(6):473-9. PMID 11182136
  22. Laffitte BA, Chao LC, Li J, Walczak R, Hummasti S, Joseph SB, Castrillo A, Wilpitz DC, Mangelsdorf DJ, Collins JL, Saez E, Tontonoz P. 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. 2003 Apr 29;100(9):5419-24. PMID 12697904
  23. Joseph SB, Castrillo A, Laffitte BA, Mangelsdorf DJ, Tontonoz P. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med. 2003 Feb;9(2):213-9. PMID 12524534
  24. Fukuchi J, Kokontis JM, Hiipakka RA, Chuu CP, Liao S. Antiproliferative effect of liver X receptor agonists on LNCaP human prostate cancer cells. Cancer Res. 2004 Nov 1;64(21):7686-9. PMID 15520170
  25. Chuu CP, Hiipakka RA, Kokontis JM, Fukuchi J, Chen RY, Liao S. Inhibition of tumor growth and progression of LNCaP prostate cancer cells in athymic mice by androgen and liver X receptor agonist. Cancer Res. 2006 Jul 1;66(13):6482-6. PMID 16818617
  26. Koldamova RP, Lefterov IM, Staufenbiel M, Wolfe D, Huang S, Glorioso JC, Walter M, Roth MG, Lazo JS. The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer's disease.J Biol Chem. 2005 Feb 11;280(6):4079-88. PMID 15557325

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