Liver X Receptor α (NR1H3)

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Introduction

LXRα and LXRβ are transcription factors commonly known as cholesterol sensors [1].  Although they are important regulators of transport and metabolism of sterols and fatty acids, whether they are direct sensors of w3-PUFAs has been questioned [2].  Expression of LXRα is restricted, whereas LXRβ is ubiquitously present.  LXRα is present in certain organs namely liver, kidney, intestine, adipose tissue and adrenals.  LXRα and β share a high degree of amino acid similarity (~80%) and are considered paralogues; as a result there are very few subtype specific agonists.  Oxysterols including 24(S), 25-epoxycholesterol, 22R-hydroxycholesterol, and 24(S)-hydroxycholesterol, are natural ligands of LXRs.  [A1] PUFAs competitively blocked activation of LXR by oxysterols [3].  This offers a potential mechanism for the ability of dietary PUFAs to decrease the synthesis and secretion of fatty acids and triglycerides in liver [3]. This suppressive effect can be eliminated by deletion and mutation of LXR responsive element (LXREs) located in the promoter region of SREBP-1c. However, others have shown that the unsaturated fatty acid suppression of SREBP-1 and its targeted lipogenic genes is independent of LXRα [4]. Perhaps the effects of fatty acids on LXR-mediated events are being mediated by a direct interaction between PPARα and LXRα [5]. In fact, several xenobiotic PPARα ligands antagonize LXR’s transcriptional activity [6].

Role of LXRβ in Cardiovascular Disease. 

There is increasing interest in LXR agonist, whether dietary or pharmaceutical, in the prevention of CVD [7].  The nonsteroidal LXR agonist, GW3965 significantly reduced atherosclerosis in murine models of hyperlipidemia [8].  Several LXR-mediated genes include those associated with cholesterol and bile acid metabolism (for example ABCA1, ABCG1, Apo-E, and CYP7A) as well as those with fatty acid synthesis and regulation (SREBP1c, LPL, FAS). Previous studies showed that activation of PPARγ induced the expression of LXRα and ABCA1, and  removed cholesterol from macrophages [9].  Hence, LXR was considered further downstream than PPARγ in reducing atherosclerosis. LXRα knockout mice were unable to respond to dietary cholesterol and failed to induce cholesterol 7-hydroxylase (Cyp7A), the rate limiting enzyme for bile acid synthesis [10].  This resulted in excessive cholesterol accumulation in the liver followed by impairment of functions.  LXRα knockout animals also have altered expression of genes associated with lipid metabolism.  Interestingly, LXRβ knockout mice were unaffected when challenged with dietary cholesterol [11].  Selective bone marrow knockouts of macrophage LXRs increase atherosclerotic lesions in ApoE-/- and LDLR-/- mice, suggesting a role as an endogenous inhibitor of atherosclerosis [8].  



References 

1. Francis GA, Fayard E, Picard F, Auwerx J: Nuclear receptors and the control of metabolism. Annu Rev Physiol 2003, 65:261-311.
2. Vanden Heuvel JP, Thompson JT, Frame SR, Gillies PJ: Differential activation of nuclear receptors by perfluorinated fatty acid analogs and natural fatty acids: a comparison of human, mouse, and rat peroxisome proliferator-activated receptor-alpha, -beta, and -gamma, liver X receptor-beta, and retinoid X receptor-alpha. Toxicol Sci 2006, 92(2):476-489.
3. Ou J, Tu H, Shan B, Luk A, DeBose-Boyd RA, Bashmakov Y, Goldstein JL, Brown MS: Unsaturated fatty acids inhibit transcription of the sterol regulatory element-binding protein-1c (SREBP-1c) gene by antagonizing ligand- dependent activation of the LXR. Proc Natl Acad Sci U S A 2001, 98(11):6027-6032.
4. Pawar A, Botolin D, Mangelsdorf DJ, Jump DB: The role of liver X receptor-alpha in the fatty acid regulation of hepatic gene expression. J Biol Chem 2003, 278(42):40736-40743.
5. Miyata KS, McCaw SE, Patel HV, Rachubinski RA, Capone JP: The orphan nuclear hormone receptor LXR alpha interacts with the peroxisome proliferator-activated receptor and inhibits peroxisome proliferator signaling. J Biol Chem 1996, 271(16):9189-9192.
6. Laffitte BA, Repa JJ, Joseph SB, Wilpitz DC, Kast HR, Mangelsdorf DJ, Tontonoz P: LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc Natl Acad Sci U S A 2001, 98(2):507-512.
7. Lund EG, Menke JG, Sparrow CP: Liver X receptor agonists as potential therapeutic agents for dyslipidemia and atherosclerosis. Arterioscler Thromb Vasc Biol 2003, 23(7):1169-1177.
8. Joseph SB, McKilligin E, Pei L, Watson MA, Collins AR, Laffitte BA, Chen M, Noh G, Goodman J, Hagger GN et al: Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc Natl Acad Sci U S A 2002, 99(11):7604-7609.
9. Chawla A, Barak Y, Nagy L, Liao D, Tontonoz P, Evans RM: PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med 2001, 7(1):48-52.
10. 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, 93(5):693-704.
11. 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, 107(5):565-573.


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