肝X受体在胆固醇代谢过程中的作用机制

陈裕; 范晓飞; 郑忠清; 王邦茂

doi:10.3969/j.issn.1001-5256.2016.05.049

肝X受体在胆固醇代谢过程中的作用机制

DOI: 10.3969/j.issn.1001-5256.2016.05.049

天津医科大学总医院消化科天津市消化病学研究所

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中图分类号: R333
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出版历程
- 出版日期: 2016-05-20

Role of liver X receptor in process of cholesterol metabolism and its mechanism of action

摘要

摘要: 胆固醇是细胞膜的组成成分,对维持机体代谢及正常的功能有着至关重要的作用。肝X受体(LXR)是肝脏中丰富表达的一种核受体,通过在肝细胞层面调控胆固醇及胆汁酸的合成、转化及转运来影响胆固醇代谢过程,在维持机体胆固醇稳态中发挥重要作用。另外,LXR能抑制食物中胆固醇在肠道的吸收,从而降低机体外源性胆固醇水平,从一定程度上降低机体总胆固醇水平,预防高胆固醇血症、胆结石等的形成。从肝脏和肠道两个层面对LXR调控胆固醇代谢的机制进行了总结。
- 胆固醇 /
- 肝X受体 /
- 胆酸类 /
- 综述
Abstract: Cholesterol is a component of cell membrane and plays a vital role in maintaining metabolism and normal functions in human body. Liver X receptor( LXR) is a nuclear receptor expressed in abundance in the liver. It influences the process of cholesterol metabolism through regulating the synthesis,transformation,and transportation of cholesterol and bile acid at the level of hepatocytes,and therefore,it plays an important role in maintaining cholesterol homeostasis in human body. In addition,LXR can inhibit the intestinal absorption of dietary cholesterol,reduce exogenous cholesterol level and total cholesterol level in human body,and prevent hypercholesterolemia and formation of gallstones. This article summarizes the mechanism of action of LXR in regulating cholesterol metabolism at both liver and intestinal levels.
- cholesterol /
- liver X receptor /
- cholic acids /
- review

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参考文献(37)

[1]WOJCICKA G,JAMROZ-WISNIEWSKA A,HOROSZEWICZ K,et al.Liver X receptors(LXRs).Part I:structure,function,regulation of activity,and role in lipid metabolism[J].Postepy Hig Med Dosw(Online),2007,61:736-759.

[2]REPA JJ,MANGELSDORF DJ.The role of orphan nuclear receptors in the regulation of cholesterol homeostasis[J].Annu Rev Cell Dev Biol,2000,16(1):459-481.

[3]WILLY PJ,UMESONO K,ONQ ES,et al.LXR,a nuclear receptor that defines a distinct retinoid response pathway[J].Genes Dev,1995,9(9):1033-1045.

[4]ALBERTI S,SCHUSTER G,PARINI P,et al.Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXR beta-deficient mice[J].J Clin Invest,2001,107(5):565-573.

[5]WANG Y,ROGERS PM,SU C,et al.Regulation of cholesterologenesis by the oxysterol receptor,LXR alpha[J].J Biol Chem,2008,283(39):26332-26339.

[6]ISHIMOTO K,TACHIBANA K,SUMITOMO M,et al.Identification of human low-density lipoprotein receptor as a novel target gene regulated by liver X receptor alpha[J].FEBS Lett,2006,580(20):4929-4933.

[7]ZELCER N,HONG C,BOYADJIAN R,et al.LXR regulates cholesterol uptake through idol-dependent ubiquitination of the LDL receptor[J].Science,2009,325(5936):100-104.

[8]WANG LJ,SONG BL.Niemann-Pick C1-like 1 and cholesterol uptake[J].Biochim Biophys Acta,2012,1821(7):964-972.

[9]DUVAL C,TOUCHE V,TAILLEUX A,et al.Niemann-Pick C1-like 1 gene expression is down-regulated by LXR activators in the intestine[J].Biochem Biophys Res Commun,2006,340(4):1259-1263.

[10]ALVARO A,ROSALES R,MASANA L,et al.Polyunsaturated fatty acids down-regulate in vitro expression of the key intestinal cholesterol absorption protein NPC1L1:no effect of monounsaturated nor saturated fatty acids[J].J Nutr Biochem,2010,21(6):518-525.

[11]BROWN JM,YU L.Opposing gatekeepers of apical sterol transport:niemann-pick c1-like 1(NPC1L1)and ATP-binding cassette transporters G5 and G8(ABCG5/ABCG8)[J].Immunol Endocr Metab Agents Med Chem,2009,9(1):18-29.

[12]BERGE KE,TIAN H,GRAF GA,et al.Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters[J].Science,2000,290(5497):1771-1775.

[13]GONZALEZ-GRANILLO M,STEFFENSEN KR,GRANADOS O,et al.Soy protein isoflavones differentially regulate liver X receptor isoforms to modulate lipid metabolism and cholesterol transport in the liver and intestine in mice[J].Diabetologia,2012,55(9):2469-2478.

[14]FREEMAN LA,KENNEDY A,WU J,et al.The orphan nuclear receptor LRH-1 activates the ABCG5/ABCG8 intergenic promoter[J].J Lipid Res,2004,45(7):1197-1206.

[15]WANG N,RANALLETTA M,MATSUURA F,et al.LXR-induced redistribution of ABCG1 to plasma membrane in macrophages enhances cholesterol mass efflux to HDL[J].Arterioscler Thromb Vasc Biol,2006,26(6):1310-1316.

[16]WANG N,YVAN-CHARVET L,LUTJOHANN D,et al.ATPbinding cassette transporters G1 and G4 mediate cholesterol and desmosterol efflux to HDL and regulate sterol accumulation in the brain[J].FASEB J,2008,22(4):1073-1082.

[17]KANNISTO K,GAFVELS M,JIANG ZY,et al.LXR driven induction of HDL-cholesterol is independent of intestinal cholesterol absorption and ABCA1 protein expression[J].Lipids,2014,49(1):71-83.

[18]CUI W,SUN Y,WANG Z,et al.Activation of liver X receptor decreases BACE1 expression and activity by reducing membrane cholesterol levels[J].Neurochem Res,2011,36(10):1910-1921.

[19]DELVECCHIO CJ,BILAN P,NAIR P,et al.LXR-induced reverse cholesterol transport in human airway smooth muscle is mediated exclusively by ABCA1[J].Am J Physiol Lung Cell Mol Physiol,2008,295(5):1949-1957.

[20]WANG H,LIU Y,ZHU L,et al.17beta-estradiol promotes cholesterol efflux from vascular smooth muscle cells through a liver X receptor alpha-dependent pathway[J].Int J Mol Med,2014,33(3):550-558.

[21]KISS E,KRANZLIN B,WAGENBLABETA K,et al.Lipid droplet accumulation is associated with an increase in hyperglycemia-induced renal damage:prevention by liver X receptors[J].Am J Pathol,2013,182(3):727-741.

[22]LO SG,MURZILLI S,SALVATORE L,et al.Intestinal specific LXR activation stimulates reverse cholesterol transport and protects from atherosclerosis[J].Cell Metab,2010,12(2):187-193.

[23]MOSTAFA AM,HAMDY NM,EI-MESALLAMY HO,et al.Glucagon-like peptide 1(GLP-1)-based therapy upregulate LXR-ABCA1ABCG1 cascade in adipocytes[J].Biochem Biophys Res Commun,2015,468(4):900-905.

[24]von ECKARDSTEIN A,HERSBERGER M,ROHRER L.Current understanding of the metabolism and biological actions of HDL[J].Curr Opin Clin Nutr Metab Care,2005,8(2):147-152.

[25]HONG C,TONTONOZ P.Liver X receptors in lipid metabolism:opportunities for drug discovery[J].Nat Rev Drug Discov,2014,13(6):433-444.

[26]JIA Y,HOANG MH,JUN HL,et al.Cyanidin,a natural flavonoid,is an agonistic ligand for liver X receptor alpha and beta and reduces cellular lipid accumulation in macrophages and hepatocytes[J].Bioorg Med Chem Lett,2013,23(14):4185-4190.

[27]NAIK SU,WANG X,DA SILVA JS,et al.Pharmacological activation of liver X receptors promotes reverse cholesterol transport in vivo[J].Circulation,2006,113(1):90-97.

[28]PINTO PR,ROCCO DD,OKUDA LS,et al.Aerobic exercise training enhances the in vivo cholesterol trafficking from macrophages to the liver independently of changes in the expression of genes involved in lipid flux in macrophages and aorta[J].Lipids Health Dis,2015,14(1):109.

[29]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.

[30]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.

[31]de BOUSSAC H,POMMIER AJ,DUFOUR J,et al.LXR,prostate cancer and cholesterol:the good,the bad and the ugly[J].Am J Cancer Res,2013,3(1):58-69.

[32] YU L,GUPTA S,XU F,et al.Expression of ABCG5 and ABCG8is required for regulation of biliary cholesterol secretion[J].J Biol Chem,2005,280(10):8742-8747.

[33]REPA JJ,BERGE KE,POMAJZL C,et al.Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta[J].J Biol Chem,2002,277(21):18793-18800.

[34]YU L,YORK J,von BERGMANN K,et al.Stimulation of cholesterol excretion by the liver X receptor agonist requires ATP-binding cassette transporters G5 and G8[J].J Biol Chem,2003,278(18):15565-15570.

[35]CALPE-BERDIEL L,ROTLLAN N,FIEVET C,et al.Liver X receptor-mediated activation of reverse cholesterol transport from macrophages to feces in vivo requires ABCG5/G8[J].J Lipid Res,2008,49(9):1904-1911.

[36]YU L,GUPTA S,XU F,et al.Expression of ABCG5 and ABCG8is required for regulation of biliary cholesterol secretion[J].J Biol Chem,2005,280(10):8742-8747.

[37]JIANG ZY,PARINI P,EGGERTSEN G,et al.Increased expression of LXR alpha,ABCG5,ABCG8,and SR-BI in the liver from normolipidemic,nonobese Chinese gallstone patients[J].J Lipid Res,2008,49(2):464-472.

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