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Future Lipidology Volume 1, 2006 - Issue 2
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Liver X receptors: new drug targets to treat Type 2 diabetes?

Knut SteffensenNOVUM, Department of Biosciences and Nutrition, Karolinska Institute, S-14157 Huddinge, Sweden, Tel.: +46 860 833 39; Fax.: +46 877 455 38, E-mail: [email protected]; [email protected]
&
Knut Jan-ÅkeNOVUM, Department of Biosciences and Nutrition, Karolinska Institute, S-14157 Huddinge, Sweden, Tel.: +46 860 833 39; Fax.: +46 877 455 38, E-mail: [email protected]; [email protected]Correspondence[email protected]
Pages 181-189 | Published online: 18 Jan 2017

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  • The first paper to describe the molecular mechanisms behind liver X receptor (LXR) signaling.
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  • The first paper to describe impaired cholesterol metabolism in LXR α-/- mice.
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  • Presents studies on LXRβ-/- mice and the differences between the LXR paralogs in cholesterol metabolism.
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  • Demonstrates that the human cytochrome P450 (CYP)7A1 gene is differently regulated at transcriptional level compared with mouse and rat.
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  • Demonstrates that LXRs increase hepatic lipogenesis and induce expression of lipogenic enzymes.
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  • The first report to describe the antidiabetic action of the LXRs. Activated LXRs reduce plasma glucose concentrations and suppress expression of genes involved in gluconeogenesis.
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  • Summarizes the biological effects of LXR signaling.
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  • Summarizes the biological effects of LXR signaling.
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  • Wang Y, Kurdi-Haidar B, Oram JF: LXR-mediated activation of macrophage stearoyl-CoA desaturase generates unsaturated fatty acids that destabilize ABCA1. J. Lipid Res. 45(5), 972–980 (2004)
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  • Demonstrates that LXRαβ-/- mice accumulate lipids in peripheral tissue and that LXRαβ-/- mice have lower highdensity lipoprotein (HDL)-cholesterol, but higher low-density lipoprotein (LDL)-cholesterol.
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  • Mak PA, Laffitte BA, Desrumaux C et al.: Regulated expression of the apolipoprotein E/C-I/C-IV/C-II gene cluster in murine and human macrophages. A critical role for nuclear liver X receptors and . J. Biol. Chem. 277(35), 31900–31908 (2002)
  • Laffitte BA, Repa JJ, Joseph SB et al.: LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc. Natl Acad. Sci. USA 98(2), 507–512 (2001)
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  • Liang Y, Jiang XC, Liu R et al.: Liver X receptors (LXRs) regulate apolipoprotein AIV-implications of the antiatherosclerotic effect of LXR agonists. Mol. Endocrinol. 18(8), 2000–2010 (2004)
  • Zhang Y, Repa JJ, Gauthier K, Mangelsdorf DJ: Regulation of lipoprotein lipase by the oxysterol receptors, LXR and LXR . J. Biol. Chem. 276(46), 43018–43024 (2001)
  • Malerod L, Juvet LK, Hanssen-Bauer A, Eskild W, Berg T: Oxysterol-activated LXR /RXR induces hSR-BI-promoter activity in hepatoma cells and preadipocytes. Biochem. Biophys. Res. Commun. 299(5), 916–923 (2002)
  • Luo Y, Tall AR: Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element. J. Clin. Invest. 105(4), 513–520 (2000)
  • Cao G, Beyer TP, Yang XP et al.: Phospholipid transfer protein is regulated by liver X receptors in vivo. J. Biol. Chem. 277(42), 39561–39565 (2002)
  • Ory DS: Nuclear receptor signaling in the control of cholesterol homeostasis: have the orphans found a home? Circ. Res. 95(7), 660–670 (2004)
  • Costet P, Luo Y, Wang N, Tall AR: Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J. Biol. Chem. 275(36), 28240–28245 (2000)
  • Kennedy MA, Venkateswaran A, Tarr PT et al.: Characterization of the human ABCG1 gene: liver X receptor activates an internal promoter that produces a novel transcript encoding an alternative form of the protein. J. Biol. Chem. 276(42), 39438–39447 (2001)
  • Repa JJ, Turley SD, Lobaccaro JA et al.: Regulation of absorption and ABC1- mediated efflux of cholesterol by RXR heterodimers. Science 289(5484), 1524–1529 (2000).
  • Demonstrates that activated LXRs increase reverse cholesterol transport and decrease cholesterol absorption in the intestine via induced expression of the ABCA1 gene.
  • Schwartz K, Lawn RM, Wade DP: ABC1 gene expression and ApoA-I-mediated cholesterol efflux are regulated by LXR. Biochem. Biophys. Res. Commun. 274(3), 794–802 (2000)
  • Venkateswaran A, Laffitte BA, Joseph SB et al.: Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR . Proc. Natl Acad. Sci. USA 97(22), 12097–12102 (2000)
  • Claudel T, Leibowitz MD, Fievet C et al.: Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor. Proc. Natl Acad. Sci. USA 98(5), 2610–2615 (2001)
  • Tangirala RK, Bischoff ED, Joseph SB et al.: Identification of macrophage liver X receptors as inhibitors of atherosclerosis. Proc. Natl Acad. Sci. USA 99(18), 11896–11901 (2002)
  • Joseph SB, McKilligin E, Pei L et al.: Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc. Natl Acad. Sci. USA 99(11), 7604–7609 (2002)
  • Terasaka N, Hiroshima A, Koieyama T et al.: T-0901317, a synthetic liver X receptor ligand, inhibits development of atherosclerosis in LDL receptor-deficient mice. FEBS Lett. 536(1–3), 6–11 (2003)
  • Yu L, York J, von Bergmann K, Lutjohann D, Cohen JC, Hobbs HH: Stimulation of cholesterol excretion by the liver X receptor agonist requires ATP-binding cassette transporters G5 and G8. J. Biol. Chem. 278(18), 15565–15570 (2003)
  • Kase ET, Wensaas AJ, Aas V et al.: Skeletal muscle lipid accumulation in Type 2 diabetes may involve the liver X receptor pathway. Diabetes 54(4), 1108–1115 (2005).
  • Demonstrates that LXRs are important regulators of lipid and glucose uptake and oxidation in muscle.
  • Gerin I, Dolinsky VW, Shackman JG et al.: LXR is required for adipocyte growth, glucose homeostasis, and cell function. J. Biol. Chem. 280(24), 23024–23031 (2005).
  • Demonstrates that LXRβ-/- mice are resistant to diet-induced obesity and are glucose intolerant owing to impaired glucose-induced insulin secretion.
  • Juvet LK, Andresen SM, Schuster GU et al.: On the role of liver X receptors in lipid accumulation in adipocytes. Mol. Endocrinol. 17(2), 172–182 (2003)
  • Kalaany NY, Gauthier KC, Zavacki AM et al.: LXRs regulate the balance between fat storage and oxidation. Cell Metab. 1(4), 231–244 (2005).
  • Demonstrates that LXRαβ-/-mice fed a high-fat diet containing cholesterol are resistant to diet-induced obesity. These mice showed increased oxygen consumption and elevated energy consumption in peripheral tissues.
  • Tobin KA, Ulven SM, Schuster GU et al.: Liver X receptors as insulin-mediating factors in fatty acid and cholesterol biosynthesis. J. Biol. Chem. 277(12), 10691–10697 (2002)
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  • Dalen KT, Ulven SM, Bamberg K, Gustafsson JA, Nebb HI: Expression of the insulin-responsive glucose transporter GLUT4 in adipocytes is dependent on liver X receptor . J. Biol. Chem. 278(48), 48283–48291 (2003)
  • Laffitte BA, Chao LC, Li J et al.: Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue. Proc. Natl Acad. Sci. USA 100(9), 5419–5424 (2003).
  • Demonstrates that activated LXRs enhance glucose-induced insulin secretion from pancreaticβ-cells.old>
  • Efanov AM, Sewing S, Bokvist K, Gromada J: Liver X receptor activation stimulates insulin secretion via modulation of glucose and lipid metabolism in pancreatic β-cells. Diabetes 53(Suppl. 3) S75–S78 (2004)
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  • Grefhorst A, van Dijk TH, Hammer A et al.: Differential effects of pharmacological liver X receptor activation on hepatic and peripheral insulin sensitivity in lean and ob/ob mice. Am. J. Physiol. Endocrinol. Metab. 289(5) E829–E838 (2005)
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  • Stulnig TM, Oppermann U, Steffensen KR, Schuster GU, Gustafsson JA: Liver X receptors downregulate 11 -hydroxysteroid dehydrogenase type 1 expression and activity. Diabetes 51(8), 2426–2433 (2002)
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