Turkiye Klinikleri Journal of Medical Sciences

.: REVIEW
Kardiyovasküler Sistemde Karaciğer X Reseptörleri
Liver X Receptors in the Cardiovascular System
Nur Banu BALa, Mecit Orhan ULUDAĞa, Emine DEMİREL YILMAZb
aFarmakoloji ABD, Gazi Üniversitesi Eczacılık Fakültesi,
bTıbbi Farmakoloji ABD, Ankara Üniversitesi Tıp Fakültesi, Ankara, TÜRKİYE
Turkiye Klinikleri J Med Sci. 2019;39(4):430-43
doi: 10.5336/medsci.2019-70199
Article Language: TR
Full Text
ÖZET
 Karaciğer X reseptörleri (LXR), hücre çekirdeğinde bulunan ve 'çekirdek reseptörleri' olarak sınıflandırılan reseptörlerdir. Bu reseptörlerin LXR alfa ve LXR beta olmak üzere iki alt tipi bulunmaktadır. LXR alfa başlıca karaciğer, kalp, damarlar, böbrek, adipoz doku ve makrofajlarda eksprese olurken, LXR beta yaygın olarak birçok dokuda eksprese edilmektedir. Bu reseptörler kolesterol ve yağ asidi metabolizmasının en önemli düzenleyicileridirler. LXR endojen (oksisteroller) veya ekzojen (T0901317, GW3965 gibi) ligandlarla uyarıldığında, retinoid X reseptörü (RXR) ile heterodimer oluşturur ve hedef genin özel DNA dizisine (LXRE; LXR yanıt elemanı) bağlanarak; kolesterolün hücre dışına atılmasında, ince bağırsaklardan emilmesinde, periferden karaciğere geri gönderilmesinde ve safra içine itrahında rol alan, birçok işlevsel proteinin gen ifadelerini değiştirerek, kolesterol homeostazını düzenlerler. Ayrıca LXR agonistleri, lipogenezde rol alan transkripsiyon faktörlerinin ekspresyonunu uyararak yağ asidi sentezini tetikler ve plazma trigliserid seviyelerinin yükselmesine ve karaciğer yağlanmasına neden olurlar. Son yıllarda LXR'lerin bu işlevlerinin yanında, farklı hedef genlerin transkripsiyonunu düzenleyerek, kalp ve damar patolojilerinde yararlı etkilerinin olduğu da ortaya konmuştur. LXR'lerin ateroskleroz, hipertansiyon, kardiyak hipertrofi, diyabet ve diyabetle ilişkili kardiyovasküler patolojilerdeki rollerini incelemek için kapsamlı araştırmalar yapılmıştır. Bu derlemede, LXR'lerin kardiyovasküler hastalıklardaki rolleri ve bu hastalıkların tedavisinde ilaç hedefi olarak önemleri ele alınmıştır.

Anahtar Kelimeler: Karaciğer X reseptörleri; kardiyovasküler sistem; ateroskleroz; hipertansiyon; miyokard iskemisi; hipertrofi; fibrozis; diyabetik kardiyomiyopati; kalp; kan damarları
ABSTRACT
 The liver X receptors (LXRs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. There are two subtypes as LXR alpha and beta. LXR alpha is primarily expressed in liver, heart, vessels, kidney, intestine, adipose tissue and macrophages, whereas LXR beta is widely expressed. These receptors are master regulators of cholesterol and lipid metabolism. When LXRs are stimulated with endogenous (oxysterols) or exogenous ligands (T0901317, GW3965 etc), they form heterodimer with retinoid X receptors and LXR-RXR heterodimers bind to their target DNA sequences (LXR response element; LXRE). In this way, LXRs regulate the cholesterol homeostasis through modulating the expression of multiple genes involved in the efflux and absorption of the cholesterol, transfer of the cholesterol from non-hepatic cells to the liver and cholesterol excretion into the bile. LXR agonists also trigger de novo fatty acid synthesis by stimulating the expression of lipogenic transcription factors and cause the elevation of plasma triglycerides and liver steatosis. In addition to these functions, it has been shown that LXRs have beneficial effects in the pathologies occurring in the heart and vessel bed through regulating the transcription of different target genes. Comprehensive researchs have been carried out to examine the roles of LXR in atherosclerosis, hypertension, cardiac hypertrophy, diabetes and diabetes-associated cardiovascular pathologies. In this review, the important roles of LXRs in cardiovascular diseases and their potential use as drug target for the treatment were summarized.

Keywords: Liver X receptors; cardiovascular system; atherosclerosis; hypertension; myocardial ischemia; hypertrophy, fibrosis, diabetic cardiomyopathy; heart; blood vessels
REFERENCES:
  1. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, et al. The nuclear receptor superfamily: the second decade. Cell. 1995;83(6):835-9. [Crossref] 
  2. McKenna NJ. Research resources for nuclear receptor signaling pathways. Mol Pharmacol. 2016;90(2):153-9. [Crossref]  [PubMed]  [PMC] 
  3. Hansen MK, Connolly TM. Nuclear receptors as drug targets in obesity, dyslipidemia and atherosclerosis. Curr Opin Investig Drugs. 2008;9(3):247-55.
  4. Geyeregger R, Zeyda M, Stulnig TM. Liver X receptors in cardiovascular and metabolic disease. Cell Mol Life Sci. 2006;63(5):524-39. [Crossref]  [PubMed] 
  5. Ma Z, Deng C, Hu W, Zhou J, Fan C, Di S, et al. Liver X receptors and their agonists: targeting for cholesterol homeostasis and cardiovascular diseases. Curr Issues Mol Biol. 2017;22:41-64. [Crossref]  [PubMed] 
  6. Tontonoz P, Mangelsdorf DJ. Liver X receptor signaling pathways in cardiovascular disease. Mol Endocrinol. 2003;17(6):985-93. [Crossref]  [PubMed] 
  7. Korach-Andre M, Gustafsson JA. Liver X receptors as regulators of metabolism. Biomol Concepts. 2015;6(3):177-90. [Crossref]  [PubMed] 
  8. Wang B, Tontonoz P. Liver X receptors in lipid signalling and membrane homeostasis. Nat Rev Endocrinol. 2018;14(8):452-63. [Crossref]  [PubMed]  [PMC] 
  9. 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;9(9):1033-45. [Crossref]  [PubMed] 
  10. Joseph SB, Castrillo A, Laffitte BA, Mangelsdorf DJ, Tontonoz P. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med. 2003;9(2):213-9. [Crossref]  [PubMed] 
  11. Repa JJ, Turley S, Lobaccaro JA, Medina J, Li L, Lustig K, et al. Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science. 2000;289(5484):1524-9. [Crossref]  [PubMed] 
  12. Venkateswaran A, Repa JJ, Lobaccaro JM, Bronson A, Mangelsdorf DJ, Edwards PA. Human white/murine ABC8 mRNA levels are highly induced in lipid-loaded macrophages. A transcriptional role for specific oxysterols. J Biol Chem. 2000;275(19):14700-7. [Crossref]  [PubMed] 
  13. Zhang L, Reue K, Fong LG, Young SG, Tontonoz P. Feedback regulation of cholesterol uptake by the LXR-IDOL-LDLR axis. Arterioscler Thromb Vasc Biol. 2012;32(11):2541-6. [Crossref]  [PubMed]  [PMC] 
  14. Venkateswaran A, Laffitte BA, Joseph SB, Mak PA, Wilpitz DC, Edwards PA, et al. Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha. Proc Natl Acad Sci U S A. 2000;97(22):12097-102. [Crossref]  [PubMed]  [PMC] 
  15. Repa JJ, Berge KE, Pomajzl C, Richardson JA, Hobbs H, Mangelsdorf DJ. Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta. J Biol Chem. 2002;277(21):18793-800. [Crossref]  [PubMed] 
  16. Brunham LR, Kruit JK, Pape TD, Parks JS, Kuipers F, Hayden MR. Tissue-specific induction of intestinal ABCA1 expression with a liver X receptor agonist raises plasma HDL cholesterol levels. Circ Res. 2006;29;99(7):672-4. [Crossref]  [PubMed] 
  17. Duval C, Touche V, Tailleux A, Fruchart JC, Fievet C, Clavey V, et al. Niemann-Pick C1 like 1 gene expression is down-regulated by LXR activators in the intestine. Biochem Biophys Res Commun. 2006;340(4):1259-63. [Crossref]  [PubMed] 
  18. Calkin AC, Tontonoz P. Liver X receptor signaling pathways and atherosclerosis. Arterioscler Thromb Vasc Biol. 2010;30(8):1513-8. [Crossref]  [PubMed]  [PMC] 
  19. Guo S, Li L, Yin H. Cholesterol homeostasis and Liver X Receptor (LXR) in atherosclerosis. Cardiovasc Hematol Disord Drug Targets. 2018;18(1):27-33. [Crossref]  [PubMed] 
  20. Shimomura I, Shimano H, Korn BS, Bashmakov Y, Horton JD. Nuclear sterol regulatory element-binding proteins activate genes responsible for the entire program of unsaturated fatty acid biosynthesis in transgenic mouse liver. J Biol Chem. 1998;273(52):35299-306. [Crossref]  [PubMed] 
  21. Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JA, Shimomura I, et al. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev. 2000;14(22):2819-30. [Crossref]  [PubMed] 
  22. Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, et al. Role of LXRs in control of lipogenesis. Genes Dev. 2000;14(22):2831-8. [Crossref]  [PubMed] 
  23. Joseph SB, McKilligin E, Pei L, Watson MA, Alan R, Collins AR, et al. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc Natl Acad Sci U S A. 2002;99(11):7604-9. [Crossref]  [PubMed]  [PMC] 
  24. Collins JL, Fivush AM, Watson MA, Galardi CM, Lewis MC, Moore LB, et al. Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. J Med Chem. 2002;45(10):1963-6. [Crossref]  [PubMed] 
  25. Hong C, Tontonoz P. Liver X receptors in lipid metabolism: opportunities for drug discovery. Nat Rev Drug Discov. 2014;13(6):433-44. [Crossref]  [PubMed] 
  26. Katz A, Udata C, Ott E, Hickey L, Burczynski ME, Burghart P, et al. Safety, pharmacokinetics, and pharmacodynamics of single doses of LXR-623, a novel liver X receptor agonist, in healthy participants. J Clin Pharmacol. 2009;49(6):643-9. [Crossref]  [PubMed] 
  27. Li X, Yeh V, Molteni V. Liver X receptor modulators: a review of recently patented compounds (2007-2009). Expert Opin Ther Pat. 2010;20(4):535-62. [Crossref]  [PubMed] 
  28. Cannon MV, Yu H, Candido WM, Dokter M, Lindstedt EL, Sillje HH, et al. The liver X receptor agonist AZ876 protects against pathological cardiac hypertrophy and fibrosis without lipogenic side effects. Eur J Heart Fail. 2015;17(3):273-82. [Crossref]  [PubMed] 
  29. van der Hoorn J, Linden D, Lindahl U, Bekkers M, Voskuilen M, Nilsson R, et al. Low dose of the liver X receptor agonist, AZ876, reduces atherosclerosis in APOE*3 Leiden mice without affecting liver or plasma triglyceride levels. Br J Pharmacol. 2011;162(7):1553-63. [Crossref]  [PubMed]  [PMC] 
  30. Yasuda T, Grillot D, Billheimer JT, Briand F, Delerive P, Huet S, et al. Tissue-specific liver X receptor activation promotes macrophage reverse cholesterol transport in vivo. Arterioscler Thromb Vasc Biol. 2010;30(4):781-6. [Crossref]  [PubMed]  [PMC] 
  31. He Q, Pu J, Yuan A, Lau WB, Gao E, Koch WJ, et al. Activation of liver-X-receptor ? but not liver-X-receptor β protects against myocardial ischemia/reperfusion injury. Circ Heart Fail. 2014;7(6):1032-41. [Crossref]  [PubMed]  [PMC] 
  32. He Q, Pu J, Yuan A, Yao T, Ying X, Zhao Y, et al. Liver X receptor agonist treatment attenuates cardiac dysfunction in type 2 diabetic db/db mice. Cardiovasc Diabetol. 2014;13:149. [Crossref]  [PubMed]  [PMC] 
  33. Kuipers I, Li J, Vreeswijk-Baudoin I, Koster J, van der Harst P, Sillje HH, et al. Activation of liver X receptors with T0901317 attenuates cardiac hypertrophy in vivo. Eur J Heart Fail. 2010;12(10):1042-50. [Crossref]  [PubMed] 
  34. Schuster GU, Parini P, Wang L, Alberti S, Steffensen KR, Hansson GK, et al. Accumulation of foam cells in liver X receptor-deficient mice. Circulation. 2002;106(9):1147-53. [Crossref]  [PubMed] 
  35. Repa JJ, Mangelsdorf DJ. The liver X receptor gene team: potential new players in atherosclerosis. Nat Med. 2002;8(11):1243-8. [Crossref]  [PubMed] 
  36. Terasaka N, Hiroshima A, Koieyama T, Ubukataa N, Morikawaa Y, Nakaib D, et al. T-0901317, a synthetic liver X receptor ligand, inhibits development of atherosclerosis in LDL receptordeficient mice. FEBS Lett. 2003;536(1-3):6-11. [Crossref] 
  37. Verschuren L, de Vries-van der Weij J, Zadelaar S, Kleemann R, Kooistra T. LXR agonist suppresses atherosclerotic lesion growth and promotes lesion regression in apoE*3Leiden mice: time course and mechanisms. J Lipid Res. 2009;50(2):301-11. [Crossref]  [PubMed] 
  38. Li G, Biju KC, Xu X, Zhou Q, Chen C, Valente AJ, et al. Macrophage LXR? gene therapy ameliorates atherosclerosis as well as hypertriglyceridemia in LDLR(-/-) mice. Gene Ther. 2011;18(8):835-41. [Crossref]  [PubMed] 
  39. Gao M, Zeng Y, Guan Y, Hu Z, Zhong D, Shen X, et al. Activation of liver X receptor attenuates endothelin-1 expression in vascular endothelial cells. Int J Biochem Cell Biol. 2012;44(12):2299-307. [Crossref]  [PubMed] 
  40. Zhu M, Fu Y, Hou Y, Wang N, Guan Y, Tang C, et al. Laminar shear stress regulates liver X receptor in vascular endothelial cells. Arterioscler Thromb Vasc Biol. 2008;28(3):527-33. [Crossref]  [PubMed] 
  41. Blaschke F, Leppanen O, Takata Y, Caglayan E, Liu J, Fishbein MC, et al. Liver X receptor agonists suppress vascular smooth muscle cell proliferation and inhibit neointima formation in balloon-injured rat carotid arteries. Circ Res. 2004;95(12):e110-23. [Crossref]  [PubMed] 
  42. Yu J, Wang Q, Wang H, Lu W, Li W, Qin Z, et al. Activation of liver X receptor enhances the proliferation and migration of endothelial progenitor cells and promotes vascular repair through PI3 K/Akt/eNOS signaling pathway activation. Vascul Pharmacol. 2014;62(3):150-61. [Crossref]  [PubMed] 
  43. Spillmann F, Van Linthout S, Miteva K, Lorenz M, Stangl V, Schultheiss HP, et al. LXR agonism improves TNF-?-induced endothelial dysfunction in the absence of its cholesterol-modulating effects. Atherosclerosis. 2014;232(1):1-9. [Crossref]  [PubMed] 
  44. Chen J, Zhao L, Sun D, Narsinh K, Li C, Zhang Z, et al. Liver X receptor activation attenuates plaque formation and improves vasomotor function of the aortic artery in atherosclerotic ApoE(-/-) mice. Inflamm Res. 2012;61(12):1299-307. [Crossref]  [PubMed] 
  45. Poulter NR, Prabhakaran D, Caulfield M. Hypertension. Lancet. 2015;386(9995):801-12. [Crossref] 
  46. Morello F, de Boer RA, Steffensen KR, Gnecchi M, Chisholm JW, Boomsma F, et al. Liver X receptors alpha and beta regulate renin expression in vivo. J Clin Invest. 2005;115(7):1913-22. [Crossref]  [PubMed]  [PMC] 
  47. Kuipers I, van der Harst P, Kuipers F, van Genne L, Goris M, Lehtonen JY, et al. Activation of liver X receptor-alpha reduces activation of the renal and cardiac renin-angiotensin-aldosterone system. Lab Invest. 2010;90(4):630-6. [Crossref]  [PubMed] 
  48. Leik CE, Carson NL, Hennan JK, Basso MD, Liu QY, Crandall DL, et al. GW3965, a synthetic liver X receptor (LXR) agonist, reduces angiotensin II-mediated pressor responses in Sprague-Dawley rats. Br J Pharmacol. 2007;151(4):450-6. [Crossref]  [PubMed]  [PMC] 
  49. Imayama I, Ichiki T, Patton D, Inanaga K, Miyazaki R, Ohtsubo H, et al. Liver X receptor activator downregulates angiotensin II type 1 receptor expression through dephosphorylation of Sp1. Hypertension. 2008;51(6):1631-6. [Crossref]  [PubMed] 
  50. Han S, Bal NB, Sadi G, Usanmaz SE, Uludag MO, Demirel-Yilmaz E. The effects of LXR agonist GW3965 on vascular reactivity and inflammation in hypertensive rat aorta. Life Sci. 2018;213:287-93. [Crossref]  [PubMed] 
  51. Bal NB, Han S, Usanmaz SE, Kiremitci S, Sadi G, Uludag O, et al. Activation of Liver X Receptors by GW3965 Attenuated Deoxycorticosterone Acetate-Salt Hypertension-Induced Cardiac Functional and Structural Changes. J Cardiovasc Pharmacol. 2019;74(2):105-17. [Crossref] 
  52. Pu J, Mintz GS, Brilakis ES, Banerjee S, Abdel-Karim AR, Maini B, et al. In vivo characterization of coronary plaques: novel findings from comparing greyscale and virtual histology intravascular ultrasound and near-infrared spectroscopy. Eur Heart J. 2012;33(3):372-83. [Crossref]  [PubMed] 
  53. Lei P, Baysa A, Nebb HI, Valen G, Skomedal T, Osnes JB, et al. Activation of Liver X receptors in the heart leads to accumulation of intracellular lipids and attenuation of ischemia-reperfusion injury. Basic Res Cardiol. 2013;108(1):323. [Crossref]  [PubMed] 
  54. Cannon MV, Sillje HH, Sijbesma JW, Vreeswijk-Baudoin I, Ciapaite J, van der Sluis B, et al. Cardiac LXR? protects against pathological cardiac hypertrophy and dysfunction by enhancing glucose uptake and utilization. EMBO Mol Med. 2015;7(9):1229-43. [Crossref]  [PubMed]  [PMC] 
  55. Wu S, Yin R, Ernest R, Li Y, Zhelyabovska O, Lu J, et al. Liver X receptors are negative regulators of cardiac hypertrophy via suppressing NF-kappaB signalling. Cardiovasc Res. 2009;84(1):119-26. [Crossref]  [PubMed]  [PMC] 
  56. Castrillo A, Joseph SB, Marathe C, Mangelsdorf DJ, Tontonoz P. Liver X receptor-dependent repression of matrix metalloproteinase-9 expression in macrophages. J Biol Chem. 2003;278(12):10443-9. [Crossref]  [PubMed] 
  57. Konstantinidis K, Whelan RS, Kitsis RN. Mechanisms of cell death in heart disease. Arterioscler Throm Vasc Biol. 2012;32(7):1552-62. [Crossref]  [PubMed]  [PMC] 
  58. Cheng Y, Feng Y, Zhu M, Yan B, Fu S, Guo J, et al. Synthetic liver X receptor agonist T0901317 attenuates high glucose-induced oxidative stress, mitochondrial damage and apoptosis in cardiomyocytes. Acta Histochem. 2014;116(1):214-21. [Crossref]  [PubMed] 
  59. He Q, Wang F, Fan Y, Wang C, Zhang J. Differential effects of and mechanisms underlying the protection of cardiomyocytes by liver-X-receptor subtypes against high glucose stress-induced injury. Biochem Biophys Res Commun. 2018;503(3):1372-7. [Crossref]  [PubMed] 
  60. Agonzalez N, Bensinger SJ, Hong C, Beceiro S, Bradley MN, Zelcer N, et al. Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity. 2009;31(2):245-58. [Crossref]  [PubMed]  [PMC] 
  61. Rebe C, Raveneau M, Chevriaux A, Lakomy D, Sberna AL, Costa A, et al. Induction of transglutaminase 2 by a liver X receptor/retinoic acid receptor alpha pathway increases the clearance of apoptotic cells by human macrophages. Circ Res. 2009;105(4):393-401. [Crossref]  [PubMed] 
  62. Cao G, Liang Y, Broderick CL, Oldham BA, Beyer TP, Schmidt RJ, et al. Antidiabetic action of a liver x receptor agonist mediated by inhibition of hepatic gluconeogenesis. J Biol Chem. 2003;278(2):1131-6. [Crossref]  [PubMed] 
  63. Grefhorst A, van Dijk TH, Hammer A, van der Sluijs FH, Havinga R, Havekes LM, 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. 2005;289(5): E829-38. [Crossref]  [PubMed] 
  64. Laffitte BA, Chao LC, Li J, Walczak R, Hummasti S, Joseph SB, 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. 2003;100(9):5419-24. [Crossref]  [PubMed]  [PMC] 
  65. Baranowski M, Zabielski P, Blachnio-Zabielska AU, Harasim E, Chabowski A, Gorski J. Insulin-sensitizing effect of LXR agonist T0901317 in high-fat fed rats is associated with restored muscle GLUT4 expression and insulin-stimulated AS160 phosphorylation. Cell Physiol Biochem. 2014;33(4):1047-57. [Crossref]  [PubMed] 
  66. Gerin I, Dolinsky VW, Shackman JG, Kennedy RT, Chiang SH, Burant CF, et al. LXRbeta is required for adipocyte growth, glucose homeostasis, and beta cell function. J Biol Chem. 2005;280(24):23024-31. [Crossref]  [PubMed] 
  67. Huynh K, Bernardo BC, McMullen JR, Ritchie RH. Diabetic cardiomyopath: mechanisms and new treatment strategies targeting antioxidant signaling pathways. Pharmacol Ther. 2014;142(3):375-415. [Crossref]  [PubMed] 
  68. Cheng Y, Liu G, Pan Q, Guo S, Yang X. Elevated expression of liver X receptor alpha (LXRalpha) in myocardium of streptozotocin-induced diabetic rats. Inflammation. 2011;34(6):698-706. [Crossref]  [PubMed] 
  69. Joseph S, Laffitte BA, Patel PH, Watson MA, Matsukuma KE, Walczak R, et al. Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J Biol Chem. 2002;277(13):11019-25. [Crossref]  [PubMed] 
  70. Lund EG, Peterson LB, Adams AD, Lam MH, Burton CA, Chin J, et al. Different roles of liver X receptor alpha and beta in lipid metabolism: effects of an alpha-selective and a dual agonist in mice deficient in each subtype. Biochem Pharmacol. 2006;71(4):453-63. [Crossref]  [PubMed] 
  71. Calkin AC, Tontonoz P. Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat Rev Mol Cell Biol. 2012;13(4):213-24. [Crossref]  [PubMed]  [PMC] 
  72. Rani H, Blum-Kaelin D, Dehmlow H, Hartman P, Jablonski P, Masciadri R, et al. Discovery of tetrahydro-cyclopenta[b]indole as selective LXRs modulator. Bioorg Med Chem Lett. 2009;19(6):1654-57. [Crossref]  [PubMed] 
  73. Kirchgessner TG, Martin R, Sleph P, Grimm D, Liu X, Lupisella J, et al. Pharmacological characterization of a novel liver x receptor agonist with partial LXRalpha activity and a favorable window in nonhuman primates. J Pharmacol Exp Ther. 2015;352(2):305-14. [Crossref]  [PubMed] 
  74. Zhang XQ, Even-Or O, Xu X, van Rosmalen M, Lim L, Gadde S, et al. Nanoparticles containing a liver X receptor agonist inhibit inflammation and atherosclerosis. Adv Healthc Mater. 2015;4(2):228-36. [Crossref]  [PubMed]  [PMC] 
  75. Guo Y, Yuan W, Yu B, Kuai R, Hu W, Morin EE, et al. Synthetic high-density lipoprotein-mediated targeted delivery of liver X receptors agonist promotes atherosclerosis regression. EBioMedicine. 2018;28:225-33. [Crossref]  [PubMed]  [PMC] 
  76. Wouters K, van Bilsen M, van Gorp PJ, Bieghs V, Lutjohann D, Kerksiek A, et al. Intrahepatic cholesterol influences progression, inhibition and reversal of non-alcoholic steatohepatitis in hyperlipidemic mice. FEBS Lett. 2010;584(5):1001-5. [Crossref]  [PubMed] 
  77. Griffett K, Welch RD, Flaveny CA, Kolar GR, Neuscwander-Tetri BA, Burris TP. The LXR inverse agonist SR9238 suppresses fibrosis in a model of nonalcoholic steatohepatitis. Mol Metab. 2015;4(4):353-7. [Crossref]  [PubMed]  [PMC] 
  78. Huang P, Kaluba B, Jiang XL, Chang S, Tang XF, Mao L, et al. Liver X receptor inverse agonist SR9243 suppresses nonalcoholic steatohepatitis intrahepatic inflammation and fibrosis. Biomed Res Int. 2018;2018:8071093. [Crossref]  [PubMed]  [PMC] 
  79. Loren J, Huang Z, Laffitte BA, Molteni V. Liver X receptor modulators: a review of recently patented compounds (2009-2012). Expert Opin Ther Pat. 2013;23(10):1317-35. [Crossref]  [PubMed] 

.: Up To Date

.: Process List

Login

 Forgot your password?

 New Registration  

Contact

Ortadoğu Reklam Tanıtım Yayıncılık Turizm Eğitim İnşaat Sanayi ve Ticaret A.Ş.

.: Address

Turkocagi Caddesi No:30 06520 Balgat / ANKARA
Phone: +90 312 286 56 56
Fax: +90 312 220 04 70
E-mail: info@turkiyeklinikleri.com

.: Manuscript Editing Department

Phone: +90 312 286 56 56/ 2
E-mail: yaziisleri@turkiyeklinikleri.com

.: English Language Redaction

Phone: +90 312 286 56 56/ 145
E-mail: tkyayindestek@turkiyeklinikleri.com

.: Marketing Sales-Project Department

Phone: +90 312 286 56 56/ 142
E-mail: reklam@turkiyeklinikleri.com

.: Subscription and Public Relations Department

Phone: +90 312 286 56 56/ 118
E-mail: abone@turkiyeklinikleri.com

.: Customer Services

Phone: +90 312 286 56 56/ 118
E-mail: satisdestek@turkiyeklinikleri.com

1. TERMS OF USE

1.1. To use the web pages with http://www.turkiyeklinikleri.com domain name or the websites reached through the sub domain names attached to the domain name (They will be collectively referred as "SITE"), please read the conditions below. If you do not accept these terms, please cease to use the "SITE." "SITE" owner reserves the right to change the information on the website, forms, contents, the "SITE," "SITE" terms of use anytime they want.

1.2. The owner of the "SITE" is Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. (From now on it is going to be referred as "Turkiye Klinikleri", shortly) and it resides at Turkocagi cad. No:30, 06520 Balgat Ankara. The services in the "SITE" are provided by "Turkiye Klinikleri."

1.3. Anyone accessing the "SITE" with or without a fee whether they are a natural person or a legal identity is considered to agree these terms of use. In this contract hereby, "Turkiye Klinikleri" may change the stated terms anytime. These changes will be published in the "SITE" periodically and they will be valid when they are published. Any natural person or legal identity benefiting from and reaching to the "SITE" are considered to be agreed to any change on hereby contract terms done by "Turkiye Klinikleri."

1.4. The "Terms of Use" hereby is published in the website with the last change on March 30th 2014 and the "SITE" is activated by enabling the access to everyone. The "Terms of Use" hereby is also a part of the any "USER Contract" was and/or will be done with the users using "Turkiye Klinikleri" services with or without a fee an inseparable.

2. DEFINITIONS

2.1. "SITE": A website offering different kind of services and context with a certain frame determined by "Turkiye Klinikleri" and it is accessible on-line on http://www.turkiyeklinikleri.com domain name and/or subdomains connected to the domain name.

2.2. USER: A natural person or a legal identity accessing to the "SITE" through online settings.

2.3. LINK: A link enabling to access to another website through the "SITE", the files, the context or through another website to the "SITE", the files and the context.

2.4. CONTEXT: Any visual, literary and auditory images published in the "Turkiye Klinikleri", "SITE" and/or any website or any accessible information, file, picture, number/figures, price, etc.

2.5. "USER CONTRACT": An electronically signed contract between a natural or a legal identity benefiting from special services "Turkiye Klinikleri" will provide and "Turkiye Klinikleri".

3. SCOPE OF THE SERVICES

3.1. "Turkiye Klinikleri" is completely free to determine the scope and quality of the services via the "SITE".

3.2. To benefit the services of "Turkiye Klinikleri" "SITE", the "USER" must deliver the features that will be specified by "Turkiye Klinikleri". "Turkiye Klinikleri" may change this necessity any time single-sided.

3.3. Not for a limited number, the services "Turkiye Klinikleri" will provide through the "SITE" for a certain price or for free are;

- Providing scientific articles, books and informative publications for health industry.

- Providing structural, statistical and editorial support to article preparation stage for scientific journals.

4. GENERAL PROVISIONS

4.1. "Turkiye Klinikleri" is completely free to determine which of the services and contents provided in the "SITE" will be charged.

4.2. People benefiting from the services provided by "Turkiye Klinikleri" and using the website can use the "SITE" only according to the law and only for personal reasons. Users have the criminal and civil liability for every process and action they take in the "SITE". Every USER agrees, declares and undertakes that they will not proceed by any function or action infringement of rights of "Turkiye Klinikleri"s and/or other third parties', they are the exclusive right holder on usage, processing, storage, made public and revealing any written, visual or auditory information reported to Turkiye Klinikleri" and/or "SITE" to the third parties. "USER" agrees and undertakes that s/he will not duplicate, copy, distribute, process, the pictures, text, visual and auditory images, video clips, files, databases, catalogs and lists within the "SITE", s/he will not be using these actions or with other ways to compete with "Turkiye Klinikleri", directly or indirectly.

4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com