肠道Na~+/胆汁酸转运体与高脂血症关系的研究
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摘要
目的:本研究通过建立高脂血症大鼠模型,以肠道Na~+/胆汁酸转运体(ileal bile acid transporter,IBAT)为研究对象,探讨肠道Na~+/胆汁酸转运体与胆汁酸代谢及高脂血症形成的相关性,为防治高脂血症提供新的依据和分子理论基础,有望为治疗胆汁酸代谢紊乱及相关性疾病提供一种新的思路。方法:取Wistar雄性大鼠(体重145±8.5g)60只,随机分为2组,每组30只:普通饮食对照组(简称对照组)、高脂饮食实验组(简称实验组)。对照组予以普通饮食,实验组予以高脂饮食(配方为:在基础饲料中加入质量分数为0.04胆固醇、0.1猪油、0.05蔗糖、0.005胆酸钠、0.002丙基硫氧嘧啶),喂食90天,建立高脂血症模型,定期取血用自动生化仪检测胆固醇含量,4-6周监测血胆固醇水平,观察建模是否达到要求。两组入选大鼠均需排除已饮用含其它类药物饮食,高脂血症﹑糖尿病﹑畸形等疾病存在。建模成功后,所用实验方法分为以下两个环节:1.分别提取对照组和实验组的空肠末端、回肠末端、盲肠及结肠近端组织的RNA,应用逆转录-聚合酶链反应(RT-polymerase chain reaction; RT-PCR)技术检测两组模型肠组织的IBAT基因表达的强度;2.取对照组和实验组的空肠末端、回肠末端、盲肠及结肠近端组织,石蜡切片后用免疫组化SP(streptavidin-perosidase)法检测两组模型肠组织的IBAT表达的强度。统计数据运用SPSS14.0 for windows统计软件包作统计学处理,P <0.05显示有统计学意义。结果: 1.电泳结果显示:实验中空肠末端、回肠末端、盲肠扩增产物都出现了内参β-actin基因的220bp扩增带和IBAT基因的355bp扩增带,且实验组IBAT基因扩增带亮度明显强于对照组。结肠近端中未见IBAT基因扩增带。半定量结果分析:利用Quantity One软件计算比较每一泳道中PCR产物条带的光密度值,计算IBAT基因与β-actin条带的光密度的相对比值,通过比较各样本IBAT基因的相对值,最终得出IBAT基因在空肠、回肠末端、盲肠组织中mRNA表达的相对含量。半定量结果的相对光密度值需每组每一实验对象同等处理条件下均重复测定3次,取其最终平均值作为统计用数据。最后结果显示:结肠近端在实验组和对照组均无表达,其余在对照组IBAT基因mRNA表达较低,空肠末端(0.88427±0.041664)、回肠末端(0.92013±0.049935)、盲肠(0.86777±0.0336157),实验组IBAT基因mRNA表达较高,空肠末端(1.12817±0.050841)、回肠末端(1.14613±0.061868)、盲肠(1.14320±0.048016)表达差异性显著,空肠近端(t=-25.6988 P<0.05)、回肠末端(t=-15.446 P<0.05)、盲肠(t=-24.007 P<0.05),均有统计学意义。
2.免疫组化SP(streptavidin-perosidase)法结果显示:在高倍显微镜镜下肠道组织中出现黄色染色颗粒为阳性细胞。每张切片随机选取5个视野,每个视野内观察100个细胞,阳性细胞≥10%为阳性,否则为阴性,利用四格表的Fisher确切概率法检验。结果显示:实验组空肠末端、回肠末端、盲肠表达阳性率分别为66.3%、78.5%、55.3%;对照组空肠末端、回肠末端、盲肠表达阳性率为10.3%、12.5%、8.95%。它们之间的差异有显著性,空肠末端IBAT基因(X2=9.631 P<0.05),回肠末端IBAT基因(X2=9.873 P<0.05),盲肠IBAT基因(X2=9.209 P<0.05)。结论:1.实验组大鼠的IBAT基因mRNA的表达较对照组明显增加。2.实验组和对照组大鼠的结肠近端中未见IBAT基因的表达。3.实验组空肠末端,回肠末端及盲肠IBAT的表达明显高于对照组,故在高脂血症动物回肠中胆汁酸的主动转运及空肠中胆汁酸的被动转运过程增强,及盲肠参与胆汁酸转运增强,进而胆汁酸摄取率增加,增加体内胆酸池大小和肝内胆固醇含量,从而引起血清胆固醇增加,加速高脂血症的形成。。
Objective: In this study, through the establishment of hyperlipidemia rats to ileum Na~+ / bile acid transporter as the research object of ileal Na~+ / bile acid transporter and bile acid metabolism and hyperlipidemia in the formation of the correlation, for the prevention and control high fat hyperlipidemia disease providing a new way of thinking.Method: Take Wistar rats ( male, weight 145±8.5g) 60 rats were randomly divided into 2 groups: normal diet control group, high fat diet experimental group. Be compared to normal diet control group, the experimental group to high fat diet . (Formula: in the basal feed Concentration 0.04 cholesterol, 0.1 lard, 0.05 sucrose, 0.005 sodium cholate, 0.002 propylthiouracil), through 90 days of feeding, the establishment of hyperlipidemia model, using of automatic biochemical analyzer blood cholesterol testing regularly, monit oring the blood cholesterol levels four to six weeks, observe whether the requirements modeling. Two groups which selected required to exclude non-Winstar type rats, whether eating food with other drugs, hyperlipidemia, diabetes, deformities or other diseases . After the success of mode ling, experimental methods used were divided into the following two aspects:
1. Extraction of the control group and experimental group ileal intestinal tissue and colon tissue of RNA, reverse transcription polymerase chain reaction detection of two model ileal intestinal tissue of IBAT gene expre- ssion intensity. 2. Extraction of the control group and experimental group ileal intestinal tissue, paraffin sections by indirect immunofluorescence after staining were detected ileal intestinal tissue model of the IBAT expression intensity. Statistical data used SPSS14.0 for windows statis- tical package X2,Fish paired t test and exact test for statistical analysis, P <0.05 indicate statistical significance. Result: 1. Electrophoresis results showed that: the experiment Ileum PCR products have emerged internal referenceβ-actin gene of 355bp amplified 220bp band and IBAT gene was amplified with the experimental group, with a brightness of IBAT gene amplification was significantly stronger than the control group. Semiquantitative results analysis: calculated using quantity One software more lanes in each PCR product band of optical density, calculated IBAT gene andβ-actin band of the optical density of the relative ratio of IBAT gene by comparing the relative value of the sample, eventually come to IBAT gene expression in ileal tissue mRNA relative content. Semiquan- titative results of the relative optical density of each of the subjects in each group required the same processing conditions are determined to repeat 3 times, whichever is the final average of data for statistical use. The final results: the experimental group gene mRNA expression in rat IBAT higher Jejunum end(1.12817±0.050841) ,Ileum end(1.14613±0.061868)、caecum(1.14320±0.048016),control rat IBAT gene mRNA expression was lower Jejunum end (0.88427±0.041664)、Ileum end(0.92013±0.049935)、caecum(0.86777±0.0336157),the expression of significant differences was statistically significant (t=-25.6988, t=-15.446 t=-24.007 P <0.05).2 Indirect immunoflu- orescence staining showed that: in the high-powered microscope, fluore- scence microscope ileal tissue particles appear yellow green staining positive cells. 5 randomly selected for each slice view, each view to obse- rve the 100 cells,≥20% positive. Use tables from the Fisher exact prob- ability test results show: the experimental group IBAT expression was 66.3%,78.5%,55.3%; the control group IBAT expression was 10.3%,12.5%,8.95% . The difference between them was significant, there was significant (X2=9.631 ,X2=9.873,X2=9.209 P <0. 05).
Conclusion: 1. Experimental group of IBAT mRNA gene expression more than control group increased. 2. Experimental group and control group in the rat colon no IBAT gene expressi on. 3.Ileal experim- ental group was significantly higher expression of IBAT, so ileum bile acid active trans port process of enhanced bile acid uptake was increased, theincreaseingin cholesterol and lipid absorption, accelerate the formation of hyperli pidemia
2.免疫组化SP(streptavidin-perosidase)法结果显示:在高倍显微镜镜下肠道组织中出现黄色染色颗粒为阳性细胞。每张切片随机选取5个视野,每个视野内观察100个细胞,阳性细胞≥10%为阳性,否则为阴性,利用四格表的Fisher确切概率法检验。结果显示:实验组空肠末端、回肠末端、盲肠表达阳性率分别为66.3%、78.5%、55.3%;对照组空肠末端、回肠末端、盲肠表达阳性率为10.3%、12.5%、8.95%。它们之间的差异有显著性,空肠末端IBAT基因(X2=9.631 P<0.05),回肠末端IBAT基因(X2=9.873 P<0.05),盲肠IBAT基因(X2=9.209 P<0.05)。结论:1.实验组大鼠的IBAT基因mRNA的表达较对照组明显增加。2.实验组和对照组大鼠的结肠近端中未见IBAT基因的表达。3.实验组空肠末端,回肠末端及盲肠IBAT的表达明显高于对照组,故在高脂血症动物回肠中胆汁酸的主动转运及空肠中胆汁酸的被动转运过程增强,及盲肠参与胆汁酸转运增强,进而胆汁酸摄取率增加,增加体内胆酸池大小和肝内胆固醇含量,从而引起血清胆固醇增加,加速高脂血症的形成。。
Objective: In this study, through the establishment of hyperlipidemia rats to ileum Na~+ / bile acid transporter as the research object of ileal Na~+ / bile acid transporter and bile acid metabolism and hyperlipidemia in the formation of the correlation, for the prevention and control high fat hyperlipidemia disease providing a new way of thinking.Method: Take Wistar rats ( male, weight 145±8.5g) 60 rats were randomly divided into 2 groups: normal diet control group, high fat diet experimental group. Be compared to normal diet control group, the experimental group to high fat diet . (Formula: in the basal feed Concentration 0.04 cholesterol, 0.1 lard, 0.05 sucrose, 0.005 sodium cholate, 0.002 propylthiouracil), through 90 days of feeding, the establishment of hyperlipidemia model, using of automatic biochemical analyzer blood cholesterol testing regularly, monit oring the blood cholesterol levels four to six weeks, observe whether the requirements modeling. Two groups which selected required to exclude non-Winstar type rats, whether eating food with other drugs, hyperlipidemia, diabetes, deformities or other diseases . After the success of mode ling, experimental methods used were divided into the following two aspects:
1. Extraction of the control group and experimental group ileal intestinal tissue and colon tissue of RNA, reverse transcription polymerase chain reaction detection of two model ileal intestinal tissue of IBAT gene expre- ssion intensity. 2. Extraction of the control group and experimental group ileal intestinal tissue, paraffin sections by indirect immunofluorescence after staining were detected ileal intestinal tissue model of the IBAT expression intensity. Statistical data used SPSS14.0 for windows statis- tical package X2,Fish paired t test and exact test for statistical analysis, P <0.05 indicate statistical significance. Result: 1. Electrophoresis results showed that: the experiment Ileum PCR products have emerged internal referenceβ-actin gene of 355bp amplified 220bp band and IBAT gene was amplified with the experimental group, with a brightness of IBAT gene amplification was significantly stronger than the control group. Semiquantitative results analysis: calculated using quantity One software more lanes in each PCR product band of optical density, calculated IBAT gene andβ-actin band of the optical density of the relative ratio of IBAT gene by comparing the relative value of the sample, eventually come to IBAT gene expression in ileal tissue mRNA relative content. Semiquan- titative results of the relative optical density of each of the subjects in each group required the same processing conditions are determined to repeat 3 times, whichever is the final average of data for statistical use. The final results: the experimental group gene mRNA expression in rat IBAT higher Jejunum end(1.12817±0.050841) ,Ileum end(1.14613±0.061868)、caecum(1.14320±0.048016),control rat IBAT gene mRNA expression was lower Jejunum end (0.88427±0.041664)、Ileum end(0.92013±0.049935)、caecum(0.86777±0.0336157),the expression of significant differences was statistically significant (t=-25.6988, t=-15.446 t=-24.007 P <0.05).2 Indirect immunoflu- orescence staining showed that: in the high-powered microscope, fluore- scence microscope ileal tissue particles appear yellow green staining positive cells. 5 randomly selected for each slice view, each view to obse- rve the 100 cells,≥20% positive. Use tables from the Fisher exact prob- ability test results show: the experimental group IBAT expression was 66.3%,78.5%,55.3%; the control group IBAT expression was 10.3%,12.5%,8.95% . The difference between them was significant, there was significant (X2=9.631 ,X2=9.873,X2=9.209 P <0. 05).
Conclusion: 1. Experimental group of IBAT mRNA gene expression more than control group increased. 2. Experimental group and control group in the rat colon no IBAT gene expressi on. 3.Ileal experim- ental group was significantly higher expression of IBAT, so ileum bile acid active trans port process of enhanced bile acid uptake was increased, theincreaseingin cholesterol and lipid absorption, accelerate the formation of hyperli pidemia
引文
1. Ors E, Ahrens N, CD, Schmitz G.Familial hypercholesterolemia and lip- oprotein(a) hyperlipidemia as independent and combined cardiovascular risk factors[J].Atheroscler Suppl. 2009 Dec 29;10 (5):74-78.
2. Trauner M, Wagner M, Fickert P, etal. Molecular regulation of hepato- biliary transport systems clinical implications for understanding and treating cholestasis[J].Clin Gastroenterol. 2005; 39 (4 Suppl2): S111-S124
3. Rembek M,Goch A,Goch J.The clinical course of acute ST elevation myocardial infarction in patients with hypertension[J] .Kardiol Pol. 2010 Feb;68(2):157-163.
4. Hou L, Lu C, Huang Y, Chen S.Effect of hyperlipidemia on the expression of circadian genes in apolipoprotein E knock out atherosclerotic mic- e[J].Lipids Health Dis. 2009 Dec 30;8: 60.
5. Soderlund S, Soro-Paavonen A, EhnholmC. Hypertriglycerid emia is associated with prebeta HDL concentrations in subjects with familial low HDL[J].Lipid Res. 2005 Aug;46(8):1643- 1651. Epub 2005 May 16.
6. Fuchs M, Lammert F, Wang DQ, etal. Sterol carrier protein 2 participa tes in hypersecretion of biliary cholesterol during gallstone formation in genetically gallstone susceptible mice [J]. Biochem, 2007; 336:33-37
7. Jones MK, Catte A, Li L, Segrest JP. Dynamics of activation of lecithin: cholesterol acyltransferase by apolipoprotein A-I[J]. Bioche- mistry.2009 Dec1;48(47):11196-210.
8. Yi W, Fu P, Fan Z, Aso H, Tian C. Mitochondrial HMG-CoA synthase partially contributes to antioxidant protection in the kidney of strokeprone spontaneously hypertensive rats[J]. Nutrition. 2010 Feb 3.
9. Czesny S, Dettmers JM, Rinchard J.Linking egg thiamine and fatty acid concentrations of Lake Michigan lake trout with early life stage mortality[J].Aquat Anim Health. 2009 Dec; 21 (4):262-71.
10. Meier PJ,Stieger B.Bile salt transporters[J]. Annu Rev Physiol 2002,64:635-661,
11. Makishima M. Nuclear receptors as targets for drug developpment: regulation of cholesterol and bile acid metabolism by nuclear receptors[J]. Pharmacol Sci. 2005; 97 (2):177-183
12. Wang DQ, Cohen DE, Carey MC. Biliary lipids and gallstone formation[J]. Lipid Res, 2008; Nov 17(7):157-163
13. Rideout TC, Harding SV, Jones PJ, Fan MZ.Guar gum and similar so- luble fibers in the regulation of cholesterol metabolism: current understan dings and future research priorit ies [J].Vasc Health Risk Manag. 2008;4 (5):1023-33. Review.
14. Roma MG, Crocenzi FA, Sanchez Pozzi EA. Hepatocellular transport in acquired cholestasis: new insights into functional, regulatory and therapeutic aspects[J].Clin Sci (Lond). 2008 May;114(9):567-588.
15. Sinha J, Chen F, Miloh T. Beta klotho and FGF-15/19 inhibit the apic- al sodium dependent bile acid transporter in enterocytes and cholangiocytes[J].Am Physiol Gastrointest Liver Physiol. 2008 Nov;295(5):G996-G 1003. Epub 2008 Sep 4.
16. Gill RK,Alrefai WA.Bile acid transporters: regulation and pathophy- siological implications. Pharm Res[J]. 2008 Oct;24 (10):1752-1759.
17. Kramer W,Girbig F,Glombik H,eta1.Identification of aligan dbin- ding site in the Na+/bile acid cotransporting protein from rabbit- ileum[J]. Biol Chem,2004;276:36020-36027.
18. Brown WV.Therapies on the horizon for cholesterol reduction[J] .Clin Cardiol,2001;24(81):24-27.
19. Alrefai WA, Gill RK.Bile acid transporters: structure, function, regul- ation and pathophysiological implications[J].Pharm Res.2007 Oct;24 (10):1803-1823.
20. Peter JC,Lecourt AC,Weckering M,etal.A pharmacologically active monoclonal antibody against the human melanocortin 4 receptor : effe- ctiveness after peripheral and central administration[J]. Pharmacol expther. 2010 Jan 29.
21. Stelzner M,Hoagland V,Somasundaram S.Distribution of bile acidabsorption and bile acid transporter gene message in the hamster ileum [J].Pflugers Arch,2000,440:157-162.
22. Dawson PA, Hubbert M, Haywood J. The heteromeric organic solute transporter alphabeta, Ostalpha Ostbeta, is an ileal basolate ral bile acid transporter[J]. Biol Chem.2005 Fe;25 280 (8):6960-6968.
23. Shneider BL.Intestinal bile acid transport:biology,physiology and pathophysiology[J].Podiatr Gastroenterol Nutr,2001;32:407-417.
24. Yen CJ, Izzo JG, Lee DF. Bile acid exposure up regulates tuberous scl- erosis complex mammalian target of rapamycin pathway in Barrett's associated esophageal adenocar cinoma[J]. Cancer Res. 2008 Apr;68(8) :2632-2640.
25. Gallup E,Dujovne C.New pharma cological agents under clinical investigation for treating disorders of lipoprotein regulation leading to atherosclerosis[J].Expert Opin Investig Drugs,2001;10:561-567.
26. Gill AK, Nakai D, Kono K.Novel nonsystemic inhibitor of ileal apical Na+ dependent bile acid transporter reduces serum cholesterol levels in hamsters and monkeys[J].Pharmacol. 2006 Jun;539(1-2):89-98. Epub 2006 Apr 7
27. Dawson PA, Hubbert M, Haywood J.The heteromeric organic solute transporter alphabeta, Ostalpha and Ostbeta, is an ileal baso lateral bile acid transporter[J]. Biol Chem. 2005 Feb 25;280(8): 6960-6968.
28. Chignard N, Mergey M, Veissiere D, eta1. Bile acid transport andregulating functions in the human biliary epithelium[J]. Hepatology. 2001; 33: 496-503.
29. Shneider BL. Intestinal bile acid transport: biology, physicology, and pathophysiology[J]. Podiatr Gastroenterol Nutr. 2005;32:407-417.
30. Trauner M, Wagner M, Fickert P, etal. Molecular regulation of hep- atobiliary transport systems clinical implications for understandingand treating cholestasis[J].Clin Gastroenterol. 2005;39 (4Suppl2): S111- S1124.
31. Kramer W,Girbig F,Glombik H,eta1.Identification of aligandbin- ding site in the Na+/bile acid cotransporting protein from rabbit ileum [J].Biol Chem,2001;276:36020-36027.
32. Fuchs R,Ishiwata T, Yamamoto T, Kawahara K.Enhanced expression of lumican inhibited the attachment and growth of human embryonic kidn ey 293 cells[J]. Exp Mol Pathol. 2010 Feb 4.
33. Hallen S,Fryklund J,Sachs G.Inhibition of the human sodiumbile acid cotransporters by side specific methanethiosul fonate sulfhydryl reagents:substrate controlled accessibility of site of inactivation[J]. Biochemistry,2000;39:6743-6750.
34. Catterall WA, Dib Ha SL, Meisler MH.Inherited neuronalion channe- lopathies: new windows on complex neuro logical diseases [J].Neurosci. 2008 Nov 12;28(46):11768-11777.
35. Roberts CK. HMG-CoA reductase, cholesterol 7alpahydroxy lase,LDL receptor, SR-B1, and ACAT in diet-induced syndrome X. Kidney Int[J]. 2004; 66(4):1503-1511
36. Tang SJ, Bergs R, Jazrawi SF, Olukoga CO, Caddedu J, Fernandez R, Scott DJ.Live video manipulator for endoscopy and natural orifice transluminal endoscopic surgery (with videos). Gastrointest Endosc[J]. 2008 Sep;68(3):559-64. Epub 2008 Jul 16.
37. BongeH,HallenS,FryklundJ,eta1.Cytostar-T scintillating ateassay for measurement of sodium dependent bile acid up take in transfected HEK-293 cells[J].Anal Biochem,2006,282:94-101.
38. Makishima M. Nuclear receptors as targets for drug developpment: regulation of cholesterol and bile acid metabolism by nuclear receptors[J]. Pharmacol Sci. 2005; 97 (2):177-183
39. Fryklund J, Roberts CK. HMG-CoA reductase, cholesterol phahydr- oxylase, LDL receptor, SR-B1, and ACAT in diet induced syndrome X[J]. Kidney Int. 2006; 66(4):1502-1511
40. Kglmeier J, Day C, Puntis JW.Clinical outcome in patients from a si- ngle region who were dependent on parenteral nutrition for 28 days or more[J].Arch Dis Child. 2008 Apr;93 (4):300-302.Epub 2008 Jan 11.
41. Eren M.The role of statins in the treatment of heart failure.Turk Kard- iyol Dern Ars[J]. 2009 Oct;37(7):501-11.
42. Jungst C, Sreejayan N, Eder MI.Lipid peroxidation and mucin secre- tagogue activity in bile of gallstone patients[J].Clin Invest. 2007 Sep;37(9):731-736.
43. Shang Q, Saumoy M, Holst JJ, Salen G, Xu G.Colesevelam improves insulin resistance in a diet induced obesity (F-DIO) rat model by increas- ing the release of GLP-1[J].Physiol Gastrointest Liver Physiol. 2010Mar; 298(3):G419-24.
44. Petrovi V, Kora A, Buza B, Vasili A.Nitric oxide regulates mitochond- rial remodelling in interscapular brown adipose tissue: ultrastructural and morphometric stereologic studies[J]. Microsc. 2008 Dec; 232(3) :542-548
45. Zhang XM, Dong L, Liu LN, Lei YM.Effect of SC-435 on the gastro- intestinal migrating myoelectric complex in guinea pigs. Zhong Nan Da Xue Xue Bao Yi Xue Ban[J]. 2005 Oct;30(5):497-503.
46. Korac A, Buzadzic B, Petrovic V.Leptin immunoexpression and inne- rvation in rat interscapular brown adipose tissue of cold acclimated rats: the effects of Larginine and LNAME[J].Folia Histochem Cytobiol.2008;46(1):103-9
47. Skibicka KP, Grill HJ.Energetic responses are triggered by caudal bra instem melanocortin receptor stimulation and mediate by local sympathetic effector circuits[J].Endocrinology. 2008 Jul;149(7):3605 -16. Epub 2008 Mar 27:1158-1162
48. Derdemezis CS, Filippatos TD, Mikhailidis DP, Elisaf MS. Effects of Plant Sterols and Stanols Beyond Low Density Lipoprotein Cholesterol Lowering[J]. Cardiovasc Pharmacol Ther. 2010 Mar 3: 112-125
49. Buchwald H,Varco RL,Marts JP,eta1.Effect of partial Ilealby pass surgery on morality and morbidity from coro Nary heart disease in patients with hypercholesterolemia.Report of the Programonthe Surgical Control of the Hyper lipidemias(POSCH) [M].N Engl J Med 2009,323:946-955
1. P. J. Meier and B. Stieger. Bile salt transporters. Annu. Rev.Physiol. 64:635–661 (2002).
2. Ping Lam, Claire L. Pearson, Carol J. Soroka, Shuhua Xu, Albert Mennone and James L. BoyerLevels of plasma membrane expression in progressiveand benign mutations of the bile salt export pump(Bsep/Abcb11) correlate with severity of choles- tatic diseases. Am J Physiol Cell Physiol, 293:1709-1716, 2007.
3. FORKER EL, LUXON BA, SNELL M, AND SHURMANTINE WO. Effect of albumin binding on the hepatic transport of rose bengal: surfacemediateddissociation of limited capacity. J Pharmacol Exp Ther223: 342–347, 1982.
4. TANIGUCHI K, WADA M, KOHNO K, NAKAMURA T, KAWABE T, KAWAKAMIM, KAGOTANI K, OKUMURA K, AKIYAMA S, AND KUWANO M. A human canalicular multispecific organic anion transporter (cMoat) gene isoverexpressed in cisplatin-resistant human cancer cell lines withdecreased drug accumulation. Cancer Res 56: 4124–4129, 1996.
5. Stieger B,Meier Y,Meier PJ.The bile salt export pump [J].Pflugers Arch,2007,453(5):61 1-620.
6. Oude Elferink RP,Paulusma CC.Function and patho[)hysiological importance of ABCB4 fMDR3 P-glycoprotein)[J].Pflugers Arch,2007,453(5):601-610.
7. KULLAK-UBLICK GA, HAGENBUCH B, STIEGER B, SCHTEINGART CD, HOFMANNAF, WOLKOFF AW, AND MEIER PJ. Molecular and functionalcharacterization of an organic anion transporting polypeptidecloned from human liver. Gastroenterology 109: 1274–1282, 1995.
8. Arl~se M,Ananthanarayanan M.Th e bile salt export pum p:molecular properties,function and regulation[J].Pflugers Arch,2004,449(2):123—131.
9. LAMMERT F, COHEN DE, PAIGEN B, CAREY MC, AND BEIER DR. Thegene encoding the multispecific organic anion transporter (Cmoat)of the hepatocyte canalicular membrane maps to mouse chromosome19. Mamm Genome 9: 87–88, 1998.
10. VAN KUIJCK MA, KOOL M, MERKX GF, GEURTS VK, BINDELS RJ, DEENPM, AND VAN OS CH. Assignment of the canalicular multispecificorganic anion transporter gene (CMOAT) to human chromosome10q24 and mouse chromosome 19D2 by fluorescent in situ hybridization.Cytogenet Cell Genet 77: 285–287, 1997.
11. HAGENBUCH B, ADLER ID, AND SCHMID TE. Molecular cloning andfunctional characterization of the mouse organic-anion- transportingpolypeptide 1 (Oatp1) and mapping of the gene tochromosomeX. Biochem J 345: 115–120, 2000.
12. Mita S, Suzuki H, Akita H, Hayashi H, Onuki R, Hofmann AF, Sugiyama Y. Vectorial transport of unconjugated and conjugated bilesalts by monolayers of LLC-PK1 cells doubly transfected with humanNTCP and BSEP or with rat Ntcp and Bsep. Am J Physiol GastrointestLiver Physiol 290: G550–G556, 2006.
13. KULLAK-UBLICK GA, STIEGER B, HAGENBUCH B, AND MEIER PJ. Hepatictransport of bile salts. Semin Liver Dis 20: 273–292, 2000.
14. MEIER PJ, ECKHARDT U, SCHROEDER A, HAGENBUCH B, AND STIEGER B.Substrate specificity of sinusoidal bile acid and organic anion uptakesystems in rat and human liver. Hepatology 26: 1667–1677,1997.
15. MEIER PJ AND STIEGER B. Bile salt transporters. Annu Rev Physiol64: 635–661, 2002.
16. Alvarez L , Jara P , Sdnchez—Sabat6 E , et a1 . Reduced hepaticexpression of farnesoid X receptor in hereditary cholestasis associated tomutation in ATP8B1[J].Hum Mol Genet,2004,13(20):2451—2460
17. Stieger B, Fattinger K, Madon J, Kullak-Ublick GA, Meier PJ. Drugandestrogen-induced cholestasis through inhibition of the hepatocellularbile salt export pump (Bsep) of rat liver. Gastroent-erology 118: 422–430,2000
18. Elamiri A, Perwaiz S, Tuchweber B, et al. Effect of mdr2 mutation with combined tandem disruption of canalicular glycoprotein transporters by cyclosporine A on bile formation in mice. Pharmacol Res 2003; 48 (5):467-472
19. Trauner M and Boyer JL. Bile salt transporters: molecular characterization, function, and regulation. Physiol Rev 2003; 83(2): 633-671
20. ?tefkováJ, Poledne R and Hubácek. ATP-binding cassette (ABC) transporters in human metabolism and diseases. Physiol Res 2004; 53(3): 235-243
21. Henkel A, Wei Z, Cohen DE, et al. Mice overexpressing hepatic Abcb11 rapidly develop cholesterol gallstones. Mamm Genome 2005; 16(12):903-908
22. Plass JR, Mol O, Heegsma J, et al. A progressive familial intrahepatic cholestasis type 2 mutation causes an unstable, temperature-sensitive bile salt export pump. J Hepatol 2004; 40(1):24-30
23. Hoda F and Green RM. Hepatic canalicular membrane transport of bile salt in C57L/J and AKR/J mice: implications for cholesterol gallstone formation. J Membr Biol 2003; 196(1):9-14
24. Lammert F, W Kullak-ublick G, Stieger B, Hagenbuch B, et al. Hepatic transport of bile salts. Sem Liver Dis 2000; 20(3):272-293
25. Roman ID, Fernandez-Moreno MD, Fueyo JA, et al. Cyclosporin A induced internalization of the bile salt export pump in isolated rat hepatocyte couplets. Toxicol Sci 2003; 71(2):276-281
26. Byrne JA, Strautnieks SS, Mieli-Vergani G, et al. The human bile salt export pump: characterization of substrate specificity and identificat- ion of inhibitors. Gastroenterology 2002; 123(5):1649-1658
27. Paul/-Magnus C,Stieger B,Meier Y,et a1.Enterohepat/c uausport of bile salts and genetics ofcholestasis[J].J Hepatol,2005,43(2):342—357.
28. Lam CW,Cheung KM,Tsui MS,et a1.A patient wi th novel ABCB1 1gene mutations with phenotypic tran sition between BRIC2 and PF—IC2[J].J Hepatol,2006,44(1):240—242.
29. KOGAN D, ANANTHANARAYANAN M, EMRE S, SUCHY FJ, AND SHNEIDERBL. The bile salt excretory pump (BSEP/SPGP) is not down-regulatedin human cholestasis associated with extrahepatic biliaryatresia (EHBA) (Abstract). Hepatology 30: 468A, 1999.
30. Hcken P.Fuchsbichler A,Wagner M,et a1.Regurgitation of bileadds from 1esky bile ducts causes sclerosiag cholangitis in Mdr2(AbcM ) knockout micB Gastroenterology,2004,127:261-274
31. VanBerge-Henegouwen GP。Venneman NG,Portincasa P,et a1.Relevance of hereditary defects in 1ipid transport proteins for thepathogenesis of eholestero1 gallstone disease.Scand JGastroen—tero1,2004,39:60 69.
32. Trauner M,Boyer JL Bile salt transporters:molecular characteriza- tion,function.and regulation.Physiol Rev,2003,83:633 671.
33. KONG FanminSUf ChUnyang,Ll Hangyu Relation of bile salt transporters BSEP ,MRP2 and NTCP tO cholelithiasis. Chin J Hepatobiliary Surg,Mar 2006,Vo1.12,No.3
34. Gerlof T.Stieger B,Hagenbuch B,et a1.The sister of P glyco-protein represents the eanalicular bile salt export pump of mam—malian 1iver.J Bio1 Chem,1998,273:10046—10050.
35. Madon J。Eckhardt U,Gerloff T,et a1.Funetiona1 expression ofthe rat 1iver canalicular iSofoITII of the multidrug resistance-associ—ated protein. FEBS Lett.1997,406:75—78.
2. Trauner M, Wagner M, Fickert P, etal. Molecular regulation of hepato- biliary transport systems clinical implications for understanding and treating cholestasis[J].Clin Gastroenterol. 2005; 39 (4 Suppl2): S111-S124
3. Rembek M,Goch A,Goch J.The clinical course of acute ST elevation myocardial infarction in patients with hypertension[J] .Kardiol Pol. 2010 Feb;68(2):157-163.
4. Hou L, Lu C, Huang Y, Chen S.Effect of hyperlipidemia on the expression of circadian genes in apolipoprotein E knock out atherosclerotic mic- e[J].Lipids Health Dis. 2009 Dec 30;8: 60.
5. Soderlund S, Soro-Paavonen A, EhnholmC. Hypertriglycerid emia is associated with prebeta HDL concentrations in subjects with familial low HDL[J].Lipid Res. 2005 Aug;46(8):1643- 1651. Epub 2005 May 16.
6. Fuchs M, Lammert F, Wang DQ, etal. Sterol carrier protein 2 participa tes in hypersecretion of biliary cholesterol during gallstone formation in genetically gallstone susceptible mice [J]. Biochem, 2007; 336:33-37
7. Jones MK, Catte A, Li L, Segrest JP. Dynamics of activation of lecithin: cholesterol acyltransferase by apolipoprotein A-I[J]. Bioche- mistry.2009 Dec1;48(47):11196-210.
8. Yi W, Fu P, Fan Z, Aso H, Tian C. Mitochondrial HMG-CoA synthase partially contributes to antioxidant protection in the kidney of strokeprone spontaneously hypertensive rats[J]. Nutrition. 2010 Feb 3.
9. Czesny S, Dettmers JM, Rinchard J.Linking egg thiamine and fatty acid concentrations of Lake Michigan lake trout with early life stage mortality[J].Aquat Anim Health. 2009 Dec; 21 (4):262-71.
10. Meier PJ,Stieger B.Bile salt transporters[J]. Annu Rev Physiol 2002,64:635-661,
11. Makishima M. Nuclear receptors as targets for drug developpment: regulation of cholesterol and bile acid metabolism by nuclear receptors[J]. Pharmacol Sci. 2005; 97 (2):177-183
12. Wang DQ, Cohen DE, Carey MC. Biliary lipids and gallstone formation[J]. Lipid Res, 2008; Nov 17(7):157-163
13. Rideout TC, Harding SV, Jones PJ, Fan MZ.Guar gum and similar so- luble fibers in the regulation of cholesterol metabolism: current understan dings and future research priorit ies [J].Vasc Health Risk Manag. 2008;4 (5):1023-33. Review.
14. Roma MG, Crocenzi FA, Sanchez Pozzi EA. Hepatocellular transport in acquired cholestasis: new insights into functional, regulatory and therapeutic aspects[J].Clin Sci (Lond). 2008 May;114(9):567-588.
15. Sinha J, Chen F, Miloh T. Beta klotho and FGF-15/19 inhibit the apic- al sodium dependent bile acid transporter in enterocytes and cholangiocytes[J].Am Physiol Gastrointest Liver Physiol. 2008 Nov;295(5):G996-G 1003. Epub 2008 Sep 4.
16. Gill RK,Alrefai WA.Bile acid transporters: regulation and pathophy- siological implications. Pharm Res[J]. 2008 Oct;24 (10):1752-1759.
17. Kramer W,Girbig F,Glombik H,eta1.Identification of aligan dbin- ding site in the Na+/bile acid cotransporting protein from rabbit- ileum[J]. Biol Chem,2004;276:36020-36027.
18. Brown WV.Therapies on the horizon for cholesterol reduction[J] .Clin Cardiol,2001;24(81):24-27.
19. Alrefai WA, Gill RK.Bile acid transporters: structure, function, regul- ation and pathophysiological implications[J].Pharm Res.2007 Oct;24 (10):1803-1823.
20. Peter JC,Lecourt AC,Weckering M,etal.A pharmacologically active monoclonal antibody against the human melanocortin 4 receptor : effe- ctiveness after peripheral and central administration[J]. Pharmacol expther. 2010 Jan 29.
21. Stelzner M,Hoagland V,Somasundaram S.Distribution of bile acidabsorption and bile acid transporter gene message in the hamster ileum [J].Pflugers Arch,2000,440:157-162.
22. Dawson PA, Hubbert M, Haywood J. The heteromeric organic solute transporter alphabeta, Ostalpha Ostbeta, is an ileal basolate ral bile acid transporter[J]. Biol Chem.2005 Fe;25 280 (8):6960-6968.
23. Shneider BL.Intestinal bile acid transport:biology,physiology and pathophysiology[J].Podiatr Gastroenterol Nutr,2001;32:407-417.
24. Yen CJ, Izzo JG, Lee DF. Bile acid exposure up regulates tuberous scl- erosis complex mammalian target of rapamycin pathway in Barrett's associated esophageal adenocar cinoma[J]. Cancer Res. 2008 Apr;68(8) :2632-2640.
25. Gallup E,Dujovne C.New pharma cological agents under clinical investigation for treating disorders of lipoprotein regulation leading to atherosclerosis[J].Expert Opin Investig Drugs,2001;10:561-567.
26. Gill AK, Nakai D, Kono K.Novel nonsystemic inhibitor of ileal apical Na+ dependent bile acid transporter reduces serum cholesterol levels in hamsters and monkeys[J].Pharmacol. 2006 Jun;539(1-2):89-98. Epub 2006 Apr 7
27. Dawson PA, Hubbert M, Haywood J.The heteromeric organic solute transporter alphabeta, Ostalpha and Ostbeta, is an ileal baso lateral bile acid transporter[J]. Biol Chem. 2005 Feb 25;280(8): 6960-6968.
28. Chignard N, Mergey M, Veissiere D, eta1. Bile acid transport andregulating functions in the human biliary epithelium[J]. Hepatology. 2001; 33: 496-503.
29. Shneider BL. Intestinal bile acid transport: biology, physicology, and pathophysiology[J]. Podiatr Gastroenterol Nutr. 2005;32:407-417.
30. Trauner M, Wagner M, Fickert P, etal. Molecular regulation of hep- atobiliary transport systems clinical implications for understandingand treating cholestasis[J].Clin Gastroenterol. 2005;39 (4Suppl2): S111- S1124.
31. Kramer W,Girbig F,Glombik H,eta1.Identification of aligandbin- ding site in the Na+/bile acid cotransporting protein from rabbit ileum [J].Biol Chem,2001;276:36020-36027.
32. Fuchs R,Ishiwata T, Yamamoto T, Kawahara K.Enhanced expression of lumican inhibited the attachment and growth of human embryonic kidn ey 293 cells[J]. Exp Mol Pathol. 2010 Feb 4.
33. Hallen S,Fryklund J,Sachs G.Inhibition of the human sodiumbile acid cotransporters by side specific methanethiosul fonate sulfhydryl reagents:substrate controlled accessibility of site of inactivation[J]. Biochemistry,2000;39:6743-6750.
34. Catterall WA, Dib Ha SL, Meisler MH.Inherited neuronalion channe- lopathies: new windows on complex neuro logical diseases [J].Neurosci. 2008 Nov 12;28(46):11768-11777.
35. Roberts CK. HMG-CoA reductase, cholesterol 7alpahydroxy lase,LDL receptor, SR-B1, and ACAT in diet-induced syndrome X. Kidney Int[J]. 2004; 66(4):1503-1511
36. Tang SJ, Bergs R, Jazrawi SF, Olukoga CO, Caddedu J, Fernandez R, Scott DJ.Live video manipulator for endoscopy and natural orifice transluminal endoscopic surgery (with videos). Gastrointest Endosc[J]. 2008 Sep;68(3):559-64. Epub 2008 Jul 16.
37. BongeH,HallenS,FryklundJ,eta1.Cytostar-T scintillating ateassay for measurement of sodium dependent bile acid up take in transfected HEK-293 cells[J].Anal Biochem,2006,282:94-101.
38. Makishima M. Nuclear receptors as targets for drug developpment: regulation of cholesterol and bile acid metabolism by nuclear receptors[J]. Pharmacol Sci. 2005; 97 (2):177-183
39. Fryklund J, Roberts CK. HMG-CoA reductase, cholesterol phahydr- oxylase, LDL receptor, SR-B1, and ACAT in diet induced syndrome X[J]. Kidney Int. 2006; 66(4):1502-1511
40. Kglmeier J, Day C, Puntis JW.Clinical outcome in patients from a si- ngle region who were dependent on parenteral nutrition for 28 days or more[J].Arch Dis Child. 2008 Apr;93 (4):300-302.Epub 2008 Jan 11.
41. Eren M.The role of statins in the treatment of heart failure.Turk Kard- iyol Dern Ars[J]. 2009 Oct;37(7):501-11.
42. Jungst C, Sreejayan N, Eder MI.Lipid peroxidation and mucin secre- tagogue activity in bile of gallstone patients[J].Clin Invest. 2007 Sep;37(9):731-736.
43. Shang Q, Saumoy M, Holst JJ, Salen G, Xu G.Colesevelam improves insulin resistance in a diet induced obesity (F-DIO) rat model by increas- ing the release of GLP-1[J].Physiol Gastrointest Liver Physiol. 2010Mar; 298(3):G419-24.
44. Petrovi V, Kora A, Buza B, Vasili A.Nitric oxide regulates mitochond- rial remodelling in interscapular brown adipose tissue: ultrastructural and morphometric stereologic studies[J]. Microsc. 2008 Dec; 232(3) :542-548
45. Zhang XM, Dong L, Liu LN, Lei YM.Effect of SC-435 on the gastro- intestinal migrating myoelectric complex in guinea pigs. Zhong Nan Da Xue Xue Bao Yi Xue Ban[J]. 2005 Oct;30(5):497-503.
46. Korac A, Buzadzic B, Petrovic V.Leptin immunoexpression and inne- rvation in rat interscapular brown adipose tissue of cold acclimated rats: the effects of Larginine and LNAME[J].Folia Histochem Cytobiol.2008;46(1):103-9
47. Skibicka KP, Grill HJ.Energetic responses are triggered by caudal bra instem melanocortin receptor stimulation and mediate by local sympathetic effector circuits[J].Endocrinology. 2008 Jul;149(7):3605 -16. Epub 2008 Mar 27:1158-1162
48. Derdemezis CS, Filippatos TD, Mikhailidis DP, Elisaf MS. Effects of Plant Sterols and Stanols Beyond Low Density Lipoprotein Cholesterol Lowering[J]. Cardiovasc Pharmacol Ther. 2010 Mar 3: 112-125
49. Buchwald H,Varco RL,Marts JP,eta1.Effect of partial Ilealby pass surgery on morality and morbidity from coro Nary heart disease in patients with hypercholesterolemia.Report of the Programonthe Surgical Control of the Hyper lipidemias(POSCH) [M].N Engl J Med 2009,323:946-955
1. P. J. Meier and B. Stieger. Bile salt transporters. Annu. Rev.Physiol. 64:635–661 (2002).
2. Ping Lam, Claire L. Pearson, Carol J. Soroka, Shuhua Xu, Albert Mennone and James L. BoyerLevels of plasma membrane expression in progressiveand benign mutations of the bile salt export pump(Bsep/Abcb11) correlate with severity of choles- tatic diseases. Am J Physiol Cell Physiol, 293:1709-1716, 2007.
3. FORKER EL, LUXON BA, SNELL M, AND SHURMANTINE WO. Effect of albumin binding on the hepatic transport of rose bengal: surfacemediateddissociation of limited capacity. J Pharmacol Exp Ther223: 342–347, 1982.
4. TANIGUCHI K, WADA M, KOHNO K, NAKAMURA T, KAWABE T, KAWAKAMIM, KAGOTANI K, OKUMURA K, AKIYAMA S, AND KUWANO M. A human canalicular multispecific organic anion transporter (cMoat) gene isoverexpressed in cisplatin-resistant human cancer cell lines withdecreased drug accumulation. Cancer Res 56: 4124–4129, 1996.
5. Stieger B,Meier Y,Meier PJ.The bile salt export pump [J].Pflugers Arch,2007,453(5):61 1-620.
6. Oude Elferink RP,Paulusma CC.Function and patho[)hysiological importance of ABCB4 fMDR3 P-glycoprotein)[J].Pflugers Arch,2007,453(5):601-610.
7. KULLAK-UBLICK GA, HAGENBUCH B, STIEGER B, SCHTEINGART CD, HOFMANNAF, WOLKOFF AW, AND MEIER PJ. Molecular and functionalcharacterization of an organic anion transporting polypeptidecloned from human liver. Gastroenterology 109: 1274–1282, 1995.
8. Arl~se M,Ananthanarayanan M.Th e bile salt export pum p:molecular properties,function and regulation[J].Pflugers Arch,2004,449(2):123—131.
9. LAMMERT F, COHEN DE, PAIGEN B, CAREY MC, AND BEIER DR. Thegene encoding the multispecific organic anion transporter (Cmoat)of the hepatocyte canalicular membrane maps to mouse chromosome19. Mamm Genome 9: 87–88, 1998.
10. VAN KUIJCK MA, KOOL M, MERKX GF, GEURTS VK, BINDELS RJ, DEENPM, AND VAN OS CH. Assignment of the canalicular multispecificorganic anion transporter gene (CMOAT) to human chromosome10q24 and mouse chromosome 19D2 by fluorescent in situ hybridization.Cytogenet Cell Genet 77: 285–287, 1997.
11. HAGENBUCH B, ADLER ID, AND SCHMID TE. Molecular cloning andfunctional characterization of the mouse organic-anion- transportingpolypeptide 1 (Oatp1) and mapping of the gene tochromosomeX. Biochem J 345: 115–120, 2000.
12. Mita S, Suzuki H, Akita H, Hayashi H, Onuki R, Hofmann AF, Sugiyama Y. Vectorial transport of unconjugated and conjugated bilesalts by monolayers of LLC-PK1 cells doubly transfected with humanNTCP and BSEP or with rat Ntcp and Bsep. Am J Physiol GastrointestLiver Physiol 290: G550–G556, 2006.
13. KULLAK-UBLICK GA, STIEGER B, HAGENBUCH B, AND MEIER PJ. Hepatictransport of bile salts. Semin Liver Dis 20: 273–292, 2000.
14. MEIER PJ, ECKHARDT U, SCHROEDER A, HAGENBUCH B, AND STIEGER B.Substrate specificity of sinusoidal bile acid and organic anion uptakesystems in rat and human liver. Hepatology 26: 1667–1677,1997.
15. MEIER PJ AND STIEGER B. Bile salt transporters. Annu Rev Physiol64: 635–661, 2002.
16. Alvarez L , Jara P , Sdnchez—Sabat6 E , et a1 . Reduced hepaticexpression of farnesoid X receptor in hereditary cholestasis associated tomutation in ATP8B1[J].Hum Mol Genet,2004,13(20):2451—2460
17. Stieger B, Fattinger K, Madon J, Kullak-Ublick GA, Meier PJ. Drugandestrogen-induced cholestasis through inhibition of the hepatocellularbile salt export pump (Bsep) of rat liver. Gastroent-erology 118: 422–430,2000
18. Elamiri A, Perwaiz S, Tuchweber B, et al. Effect of mdr2 mutation with combined tandem disruption of canalicular glycoprotein transporters by cyclosporine A on bile formation in mice. Pharmacol Res 2003; 48 (5):467-472
19. Trauner M and Boyer JL. Bile salt transporters: molecular characterization, function, and regulation. Physiol Rev 2003; 83(2): 633-671
20. ?tefkováJ, Poledne R and Hubácek. ATP-binding cassette (ABC) transporters in human metabolism and diseases. Physiol Res 2004; 53(3): 235-243
21. Henkel A, Wei Z, Cohen DE, et al. Mice overexpressing hepatic Abcb11 rapidly develop cholesterol gallstones. Mamm Genome 2005; 16(12):903-908
22. Plass JR, Mol O, Heegsma J, et al. A progressive familial intrahepatic cholestasis type 2 mutation causes an unstable, temperature-sensitive bile salt export pump. J Hepatol 2004; 40(1):24-30
23. Hoda F and Green RM. Hepatic canalicular membrane transport of bile salt in C57L/J and AKR/J mice: implications for cholesterol gallstone formation. J Membr Biol 2003; 196(1):9-14
24. Lammert F, W Kullak-ublick G, Stieger B, Hagenbuch B, et al. Hepatic transport of bile salts. Sem Liver Dis 2000; 20(3):272-293
25. Roman ID, Fernandez-Moreno MD, Fueyo JA, et al. Cyclosporin A induced internalization of the bile salt export pump in isolated rat hepatocyte couplets. Toxicol Sci 2003; 71(2):276-281
26. Byrne JA, Strautnieks SS, Mieli-Vergani G, et al. The human bile salt export pump: characterization of substrate specificity and identificat- ion of inhibitors. Gastroenterology 2002; 123(5):1649-1658
27. Paul/-Magnus C,Stieger B,Meier Y,et a1.Enterohepat/c uausport of bile salts and genetics ofcholestasis[J].J Hepatol,2005,43(2):342—357.
28. Lam CW,Cheung KM,Tsui MS,et a1.A patient wi th novel ABCB1 1gene mutations with phenotypic tran sition between BRIC2 and PF—IC2[J].J Hepatol,2006,44(1):240—242.
29. KOGAN D, ANANTHANARAYANAN M, EMRE S, SUCHY FJ, AND SHNEIDERBL. The bile salt excretory pump (BSEP/SPGP) is not down-regulatedin human cholestasis associated with extrahepatic biliaryatresia (EHBA) (Abstract). Hepatology 30: 468A, 1999.
30. Hcken P.Fuchsbichler A,Wagner M,et a1.Regurgitation of bileadds from 1esky bile ducts causes sclerosiag cholangitis in Mdr2(AbcM ) knockout micB Gastroenterology,2004,127:261-274
31. VanBerge-Henegouwen GP。Venneman NG,Portincasa P,et a1.Relevance of hereditary defects in 1ipid transport proteins for thepathogenesis of eholestero1 gallstone disease.Scand JGastroen—tero1,2004,39:60 69.
32. Trauner M,Boyer JL Bile salt transporters:molecular characteriza- tion,function.and regulation.Physiol Rev,2003,83:633 671.
33. KONG FanminSUf ChUnyang,Ll Hangyu Relation of bile salt transporters BSEP ,MRP2 and NTCP tO cholelithiasis. Chin J Hepatobiliary Surg,Mar 2006,Vo1.12,No.3
34. Gerlof T.Stieger B,Hagenbuch B,et a1.The sister of P glyco-protein represents the eanalicular bile salt export pump of mam—malian 1iver.J Bio1 Chem,1998,273:10046—10050.
35. Madon J。Eckhardt U,Gerloff T,et a1.Funetiona1 expression ofthe rat 1iver canalicular iSofoITII of the multidrug resistance-associ—ated protein. FEBS Lett.1997,406:75—78.