靶向肝X受体的抗动脉粥样硬化药物研究进展
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摘要
肝X受体(LXR)是机体胆固醇稳态维持的重要调控因子,通过调控下游靶基因表达,参与调节各组织中的胆固醇代谢。LXR激动剂能够促进胆固醇逆向转运,发挥抗动脉粥样硬化作用,具有潜在治疗心血管疾病的作用。本文围绕近年来新型LXR激动剂,从不同来源、特点和作用机制等角度对其发挥抗动脉粥样硬化作用进行综述。
Liver X receptors(LXRs) are nuclear factors and play important roles in the regulation of cholesterol homeostasis in the body.LXRs regulate cholesterol metabolism in different tissues through regulating their target genes.LXR agonists can promote the reverse cholesterol transport in order to inhibit atherosclerosis,and have potential therapeutic effects on cardiovascular diseases.In this paper,the new LXR agonists in recent years are reviewed for their anti-atherosclerotic effects from different sources,characteristics and mechanisms.
Liver X receptors(LXRs) are nuclear factors and play important roles in the regulation of cholesterol homeostasis in the body.LXRs regulate cholesterol metabolism in different tissues through regulating their target genes.LXR agonists can promote the reverse cholesterol transport in order to inhibit atherosclerosis,and have potential therapeutic effects on cardiovascular diseases.In this paper,the new LXR agonists in recent years are reviewed for their anti-atherosclerotic effects from different sources,characteristics and mechanisms.
引文
[1]Lu H,Daugherty A.Atherosclerosis[J].Arterioscler Thromb Vasc Biol,2015,35(3):485-491.
[2]Viola J,Soehnlein O.Atherosclerosis-A matter of unresolved inflammation[J].Semin Immunol,2015,27(3):184-193.
[3]Hong C,Tontonoz P.Liver X receptors in lipid metabolism:opportunities for drug discovery[J].Nat Rev Drug Discov,2014,13(6):433-444.
[4]Venkateswaran A,Laffitte BA,Joseph SB,et al.Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha[J].Proc Natl Acad Sci,2000,97(22):12097-12102.
[5]Joseph SB,Mckilligin E,Pei L,et al.Synthetic LXRligand inhibits the development of atherosclerosis in mice[J].Proc Natl Acad Sci,2002,99(11):7604-7609.
[6]Wang X,Collins HL,Ranalletta M,et al.Macrophage ABCA1 and ABCG1,but not SR-BI,promote macrophage reverse cholesterol transport in vivo[J].J Clin Invest,2007,117(8):2216-2224.
[7]Rasheed A,Cummins CL.Beyond the foam cell:the role of LXRs in preventing atherogenesis[J].Int J Mol Sci,2018,19(8):1-20.
[8]Wang B,Tontonoz P.Liver X receptors in lipid signalling and membrane homeostasis[J].Nat Rev Endocrinol,2018,14(6):452-463.
[9]李涛,向蕾,涂剑.肝X受体-胆固醇逆转运与炎症的共同平台[J].中国动脉硬化杂志,2014,22(4):417-420.
[10]Yu XH,Qian K,Jiang N,et al.ABCG5/ABCG8 in cholesterol excretion and atherosclerosis[J].Clin Chim Acta,2014,428(1):82-88.
[11]Repa JJ,Liang G,Ou J,et al.Regulation of mouse sterol regulatory element-binding protein-1c gene(SREBP-1c)by oxysterol receptors,LXRalpha and LXRbeta[J].Genes Dev,2000,14(22):2819-2830.
[12]Janowski BA,Willy PJ,Devi TR,et al.An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha[J].Nature,1996,383(6602):728-731.
[13]Lehmann JM,Kliewer SA,Moore LB,et al.Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway[J].J Biol Chem,1997,272(6):3137-3140.
[14]Beltowski J,Semczuk A.Liver X receptor(LXR)and the reproductive system:a potential novel target for therapeutic intervention[J].Pharmacol Rep,2010,62(1):15-27.
[15]Schaffer S,Tandon R,Zipse H,et al.Stereo specific platelet inhibition by the natural LXR agonist 22(R)-OH-cholesterol and its fluorescence labelling with preserved bioactivity and chiral handling in macrophages[J].Biochem Pharmacol,2013,86(2):279-285.
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[19]Wong J,Quinn CM,Gelissen IC,et al.Endogenous 24(S),25-epoxycholesterol fine-tunes acute control of cellular cholesterol homeostasis[J].J Biol Chem,2008,283(2):700-707.
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[21]Song C,Hiipakka RA,Liao S.Selective activation of liver X receptor alpha by 6alpha-hydroxy bile acids and analogs[J].Steroids,2000,65(8):423-427.
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[36]Jun HJ,Hoang MH,Yeo SK,et al.Induction of ABCA1and ABCG1 expression by the liver X receptor modulator cineole in macrophages[J].Bioorg Med Chem Lett,2013,23(2):579-583.
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[45]Li N,Wang X,Xu Y,et al.Identification of a novel liver X receptor agonist that regulates the expression of key cholesterol homeostasis genes with distinct pharmacological characteristics[J].Mol Pharmacol,2017,91(4):264-276.
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[47]Yasuda T,Grillot D,Billheimer JT,et al.Tissue-specific liver X receptor activation promotes macrophage reverse cholesterol transport in vivo[J].Arterioscler Thromb Vasc Biol,2010,30(4):781-786.
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[49]Levin N,Bischoff ED,Daige CL,et al.Macrophage liver X receptor is required for antiatherogenic activity of LXRagonists[J].Arterioscler Thromb Vasc Biol,2005,25(1):135-142.
[50]Van Der Stoep M,Li Z,Calpe-Berdiel L,et al.Elimination of macrophages drives LXR-induced regression both in initial and advanced stages of atherosclerotic lesion development[J].Biochem Pharmacol,2013,86(11):1594-1602.
[51]Feig JE,Pineda-Torra I,Sanson M,et al.LXR promotes the maximal egress of monocyte-derived cells from mouse aortic plaques during atherosclerosis regression[J].J Clin Invest,2010,120(12):4415-4424.
[52]Verschuren L,De Vries-Van Der Weij J,Zadelaar S,et al.LXR agonist suppresses atherosclerotic lesion growth and promotes lesion regression in apo E*3Leiden mice:time course and mechanisms[J].J Lipid Res,2009,50(2):301-311.
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[54]Quinet EM,Basso MD,Halpern AR,et al.LXR ligand lowers LDL cholesterol in primates,is lipid neutral in hamster,and reduces atherosclerosis in mouse[J].JLipid Res,2009,50(12):2358-2370.
[55]Kirchgessner TG,Sleph P,Ostrowski J,et al.Beneficial and adverse effects of an LXR agonist on human lipid and lipoprotein metabolism and circulating neutrophils[J].Cell Metab,2016,24(2):223-233.
[56]Peet DJ,Turley SD,Ma W,et al.Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha[J].Cell,1998,93(5):693-704.
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[2]Viola J,Soehnlein O.Atherosclerosis-A matter of unresolved inflammation[J].Semin Immunol,2015,27(3):184-193.
[3]Hong C,Tontonoz P.Liver X receptors in lipid metabolism:opportunities for drug discovery[J].Nat Rev Drug Discov,2014,13(6):433-444.
[4]Venkateswaran A,Laffitte BA,Joseph SB,et al.Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha[J].Proc Natl Acad Sci,2000,97(22):12097-12102.
[5]Joseph SB,Mckilligin E,Pei L,et al.Synthetic LXRligand inhibits the development of atherosclerosis in mice[J].Proc Natl Acad Sci,2002,99(11):7604-7609.
[6]Wang X,Collins HL,Ranalletta M,et al.Macrophage ABCA1 and ABCG1,but not SR-BI,promote macrophage reverse cholesterol transport in vivo[J].J Clin Invest,2007,117(8):2216-2224.
[7]Rasheed A,Cummins CL.Beyond the foam cell:the role of LXRs in preventing atherogenesis[J].Int J Mol Sci,2018,19(8):1-20.
[8]Wang B,Tontonoz P.Liver X receptors in lipid signalling and membrane homeostasis[J].Nat Rev Endocrinol,2018,14(6):452-463.
[9]李涛,向蕾,涂剑.肝X受体-胆固醇逆转运与炎症的共同平台[J].中国动脉硬化杂志,2014,22(4):417-420.
[10]Yu XH,Qian K,Jiang N,et al.ABCG5/ABCG8 in cholesterol excretion and atherosclerosis[J].Clin Chim Acta,2014,428(1):82-88.
[11]Repa JJ,Liang G,Ou J,et al.Regulation of mouse sterol regulatory element-binding protein-1c gene(SREBP-1c)by oxysterol receptors,LXRalpha and LXRbeta[J].Genes Dev,2000,14(22):2819-2830.
[12]Janowski BA,Willy PJ,Devi TR,et al.An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha[J].Nature,1996,383(6602):728-731.
[13]Lehmann JM,Kliewer SA,Moore LB,et al.Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway[J].J Biol Chem,1997,272(6):3137-3140.
[14]Beltowski J,Semczuk A.Liver X receptor(LXR)and the reproductive system:a potential novel target for therapeutic intervention[J].Pharmacol Rep,2010,62(1):15-27.
[15]Schaffer S,Tandon R,Zipse H,et al.Stereo specific platelet inhibition by the natural LXR agonist 22(R)-OH-cholesterol and its fluorescence labelling with preserved bioactivity and chiral handling in macrophages[J].Biochem Pharmacol,2013,86(2):279-285.
[16]Okabe A,Urano Y,Itoh S,et al.Adaptive responses induced by 24S-hydroxycholesterol through liver X receptor pathway reduce 7-ketocholesterol-caused neuronal cell death[J].Redox Biol,2013,2(12):28-35.
[17]Bjorkhem I.Crossing the barrier:oxysterols as cholesterol transporters and metabolic modulators in the brain[J].JIntern Med,2006,260(6):493-508.
[18]Chen W,Chen G,Head DL,et al.Enzymatic reduction of oxysterols impairs LXR signaling in cultured cells and the livers of mice[J].Cell Metab,2007,5(1):73-79.
[19]Wong J,Quinn CM,Gelissen IC,et al.Endogenous 24(S),25-epoxycholesterol fine-tunes acute control of cellular cholesterol homeostasis[J].J Biol Chem,2008,283(2):700-707.
[20]Yang C,Mcdonald JG,Patel A,et al.Sterol intermediates from cholesterol biosynthetic pathway as liver X receptor ligands[J].J Biol Chem,2006,281(38):27816-27826.
[21]Song C,Hiipakka RA,Liao S.Selective activation of liver X receptor alpha by 6alpha-hydroxy bile acids and analogs[J].Steroids,2000,65(8):423-427.
[22]Endo-Umeda K,Aoyama A,Shimizu M,et al.1alphaHydroxy derivatives of 7-dehydrocholesterol are selective liver X receptor modulators[J].J Steroid Biochem Mol Biol,2017,9(172):136-148.
[23]Huang C.Natural modulators of liver X receptors[J].JIntegr Med,2014,12(2):76-85.
[24]Komati R,Spadoni D,Zheng S,et al.Ligands of therapeutic utility for the liver X receptors[J].Molecules,2017,22(1):1-24.
[25]Plat J,Mensink RP.Increased intestinal ABCA1 expression contributes to the decrease in cholesterol absorption after plant stanol consumption[J].FASEB J,2002,16(10):1248-1253.
[26]Plosch T,Kruit JK,Bloks VW,et al.Reduction of cholesterol absorption by dietary plant sterols and stanols in mice is independent of the Abcg5/8 transporter[J].JNutr,2006,136(8):2135-2140.
[27]Hoang MH,Jia Y,Jun HJ,et al.Fucosterol is a selective liver X receptor modulator that regulates the expression of key genes in cholesterol homeostasis in macrophages,hepatocytes,and intestinal cells[J].J Agric Food Chem,2012,60(46):11567-11575.
[28]Kaneko E,Matsuda M,Yamada Y,et al.Induction of intestinal ATP-binding cassette transporters by a phytosterolderived liver X receptor agonist[J].J Biol Chem,2003,278(38):36091-36098.
[29]Traves PG,Hortelano S,Zeini M,et al.Selective activation of liver X receptors by acanthoic acid-related diterpenes[J].Mol Pharmacol,2007,71(6):1545-1553.
[30]Kotani H,Tanabe H,Mizukami H,et al.Identification of a naturally occurring rexinoid,honokiol,that activates the retinoid X receptor[J].J Nat Prod,2010,73(8):1332-1336.
[31]Singh SB,Ondeyka J G,Liu W,et al.Discovery and development of dimeric podocarpic acid leads as potent agonists of liver X receptor with HDL cholesterol raising activity in mice and hamsters[J].Bioorg Med Chem Lett,2005,15(11):2824-2828.
[32]Park SH,Paek JH,Shin D,et al.Purple perilla extracts with alpha-asarone enhance cholesterol efflux from oxidized LDL-exposed macrophages[J].Int J Mol Med,2015,35(4):957-965.
[33]Jun HJ,Hoang MH,Lee JW,et al.Iristectorigenin B isolated from Belamcanda chinensis is a liver X receptor modulator that increases ABCA1 and ABCG1 expression in macrophage RAW 264.7 cells[J].Biotechnol Lett,2012,34(12):2213-2221.
[34]Hoang MH,Jia Y,Jun HJ,et al.Ethyl 2,4,6-trihydroxybenzoate is an agonistic ligand for liver X receptor that induces cholesterol efflux from macrophages without affecting lipid accumulation in Hep G2 cells[J].Bioorg Med Chem Lett,2012,22(12):4094-4099.
[35]Tamura S,Okada M,Kato S,et al.Ouabagenin is a naturally occurring LXR ligand without causing hepatic steatosis as a side effect[J].Sci Rep,2018,8(1):2305-2320.
[36]Jun HJ,Hoang MH,Yeo SK,et al.Induction of ABCA1and ABCG1 expression by the liver X receptor modulator cineole in macrophages[J].Bioorg Med Chem Lett,2013,23(2):579-583.
[37]Bramlett KS,Houck KA,Borchert KM,et al.A natural product ligand of the oxysterol receptor,liver X receptor[J].J Pharmacol Exp Ther,2003,307(1):291-296.
[38]Ondeyka JG,Jayasuriya H,Herath KB,et al.Steroidal and triterpenoidal fungal metabolites as ligands of liver Xreceptors[J].J Antibiot(Tokyo),2005,58(9):559-565.
[39]Collins JL,Fivush AM,Watson MA,et al.Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines[J].J Med Chem,2002,45(10):1963-1966.
[40]Schultz JR,Tu H,Luk A,et al.Role of LXRs in control of lipogenesis[J].Genes Dev,2000,14(22):2831-2838.
[41]El-Gendy BEM,Goher SS,Hegazy LS,et al.Recent advances in the medicinal chemistry of liver X receptors[J/OL].J Med Chem,2018,30.Doi:10.1021/acs.jmedchem.8b00045.
[42]Katz A,Udata C,Ott E,et al.Safety,pharmacokinetics,and pharmacodynamics of single doses of LXR-623,a novel liver X-receptor agonist,in healthy participants[J].J Clin Pharmacol,2009,49(6):643-649.
[43]Li X,Yeh V,Molteni V.Liver X receptor modulators:a review of recently patented compounds(2007-2009)[J].Expert Opin Ther Pat,2010,20(4):535-562.
[44]Loren J,Huang Z,Laffitte BA,et al.Liver X receptor modulators:a review of recently patented compounds(2009-2012)[J].Expert Opin Ther Pat,2013,23(10):1317-1335.
[45]Li N,Wang X,Xu Y,et al.Identification of a novel liver X receptor agonist that regulates the expression of key cholesterol homeostasis genes with distinct pharmacological characteristics[J].Mol Pharmacol,2017,91(4):264-276.
[46]Hu B,Unwalla RJ,Goljer I,et al.Identification of phenylsulfone-substituted quinoxaline(WYE-672)as a tissue selective liver X-receptor(LXR)agonist[J].J Med Chem,2010,53(8):3296-3304.
[47]Yasuda T,Grillot D,Billheimer JT,et al.Tissue-specific liver X receptor activation promotes macrophage reverse cholesterol transport in vivo[J].Arterioscler Thromb Vasc Biol,2010,30(4):781-786.
[48]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[J].FEBSLett,2003,536(1):6-11.
[49]Levin N,Bischoff ED,Daige CL,et al.Macrophage liver X receptor is required for antiatherogenic activity of LXRagonists[J].Arterioscler Thromb Vasc Biol,2005,25(1):135-142.
[50]Van Der Stoep M,Li Z,Calpe-Berdiel L,et al.Elimination of macrophages drives LXR-induced regression both in initial and advanced stages of atherosclerotic lesion development[J].Biochem Pharmacol,2013,86(11):1594-1602.
[51]Feig JE,Pineda-Torra I,Sanson M,et al.LXR promotes the maximal egress of monocyte-derived cells from mouse aortic plaques during atherosclerosis regression[J].J Clin Invest,2010,120(12):4415-4424.
[52]Verschuren L,De Vries-Van Der Weij J,Zadelaar S,et al.LXR agonist suppresses atherosclerotic lesion growth and promotes lesion regression in apo E*3Leiden mice:time course and mechanisms[J].J Lipid Res,2009,50(2):301-311.
[53]Hayashi T,Kotani H,Yamaguchi T,et al.Endothelial cellular senescence is inhibited by liver X receptor activation with an additional mechanism for its atheroprotection in diabetes[J].Proc Natl Acad Sci,2014,111(3):1168-1173.
[54]Quinet EM,Basso MD,Halpern AR,et al.LXR ligand lowers LDL cholesterol in primates,is lipid neutral in hamster,and reduces atherosclerosis in mouse[J].JLipid Res,2009,50(12):2358-2370.
[55]Kirchgessner TG,Sleph P,Ostrowski J,et al.Beneficial and adverse effects of an LXR agonist on human lipid and lipoprotein metabolism and circulating neutrophils[J].Cell Metab,2016,24(2):223-233.
[56]Peet DJ,Turley SD,Ma W,et al.Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha[J].Cell,1998,93(5):693-704.
[57]Quinet EM,Savio DA,Halpern AR,et al.Liver X receptor(LXR)-beta regulation in LXRalpha-deficient mice:implications for therapeutic targeting[J].Mol Pharmacol,2006,70(4):1340-1349.
[58]Van Der Hoorn J,Linden D,Lindahl U,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[J].Br J Pharmacol,2011,162(7):1553-1563.
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