第五节胆固醇调节元件结合蛋白
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胆固醇调节元件结合蛋白（SREBPs），是一类能与胆固醇调节元件1（SRE-1）发生特异性结合的“碱性螺旋-环-螺旋-亮氨酸拉链”（bHLH-ZZP）蛋白。在细胞内缺乏胆固醇的情况下，SREBPs通过和SRE-1的结合，激活SRE-1的基因，使其翻译增强，发挥生理功能。
一、胆固醇调节元件1的功能和定位
编码低密度脂蛋白受体（LDL-R）的基因5'侧翼区，具有一个长10个碱基对的胆固醇调节元件1（sterol regulatory element 1,SRE-1）。SRE-1是一个条件正性调节元件，仅在细胞内胆固醇缺乏的条件下，才被激活。在其他的胆固醇调节基因如羟甲基戊二酸单酰CoA合酶（HMGCoA synthase ）基因的启动子中也含有SRE-1，而在羟甲基戊二酸单酰CoA还原酶（HMGCoA reductase ）基因的启动子中含有类似于SRE-1的胆固醇调节元件（SRE）。SRE-1通过调节LDL-R基因、HMGCoA合酶基因的翻译，控制细胞对外源性胆固醇的摄取量和内源性胆固醇的合成速率，调节细胞内胆固醇含量。SRE-1在LDL-R基因5'侧翼区的定位见图7-9。
图7-9 +1表示翻译起始位点，T/A表示TATA盒，空心箭头表示
重复区，重复区1、重复区3可能和Sp1（一种正性翻译因子）结合。重复区2内含有SRE-1。
二、SREBPs的发现和命名
1989年，Tripathi B.Rajavashisth发现了一种能和SRE结合的锌脂蛋白。1993年，Michael R.Briggs等人，利用离子交换层析、凝胶过滤和DNA亲和层析的方法，从人类宫颈癌细胞（Hela细胞）核的提取物中分离出了这一组能与SRE-1结合的蛋白质，并将其命名为胆固醇调节元件结合蛋白（sterol regulatory element-binding proteins, SREBPs）。SREBPs在细胞胆固醇缺乏的情况下，通过和SRE-1的结合，激活LDLR基因、HMGCoA合酶基因的翻译。
三、SREBPs的结构和分类 SREBPs具有“碱性螺旋-环-螺旋-亮氨酸拉链”（basic helix-loop-helix-leucine zipper, bHLH-ZIP）结构，是bHLH-ZIP蛋白系列的一种。bHLH-ZIP蛋白包含一系列能特异性地和含E盒（E box, CANNTG）的DNA结合的蛋白质，例如：调节免疫球蛋白基因翻译的TFE3，致肿瘤蛋白Myc等。SREBPs虽是bHLH-ZIP蛋白中的一种，但又不同于其他的bHLH-ZIP蛋白。一方面，SREBPs分子量大，含1140个左右的氨基酸残基；另一方面，SREBPs不识别E盒（E box）而特定地识别SRE-1中直接重复的“CAC”序列。
迄今为止，发现有两种SREBPs。一种称SREBP-1，另一种称SREBP-2
。SREBP-1又由于其mRNA剪接方式的不同，以三种功能上完全相同，组成上略有不同的形式大量存在，这三种形式的蛋白分别称为SREBP-1a、SREBP-1b、SREBP-1c。其中，SREBP-1a是SREBP-1的主要存在形式，故本文以SREBP-1a为例来描述SREBP-1。SREBP-1a含1147个氨基酸残基。分子量为125kD。至今，还没有发现SREBP-2存在多种不同的剪接后蛋白。SREBP-2含1141个氨基酸残基，分子量为121kD，与SREBP-1a之间有47%的同源性，含高度保守的bHLH-ZIP区，和SREBP-1a的bHLH-ZIP区有71%的一致性。但是SREBP-2含有不同SREBP-1a的谷氨酸富集区（在121个氨基酸残基中含多于27%的谷氨酸残基。SREBP-1a和SREBP-2的氨基酸序列和功能域结构之间的比较参见图7-10（A、B、C）。
图7-10 A：SREBP-2和SREBP-1a氨基酸序列之间的比较
“--”表示二者的相同部分
图7-10 B：SREBP-2和SREBP-1a的bHLH区（粗横线所示）的比较
四、SREBPs的生理功能
两种SREBPs利用位于其氨基酸残基470～570之间的疏水序列，附着于内质网膜和核膜，在氨基端的470个氨基酸残基组成的肽链中，均含“碱性螺旋-环-螺旋-亮氨酸拉链”的核心结构，使蛋白质能形成均一二聚体，并能和SRE-1结合。两种蛋白质氨基端一侧的结构中，都有酸性区域，可能作为DNA翻译的增强子。当人或仓鼠细胞在缺乏胆固醇的环境中培养时，蛋白酶在亮氨酸拉链和膜间的附着区处裂解SREBPs，并从膜上释放出水溶性的氨基端的裂解片段，这一片段约含470个氨基酸残基，表现分子量为68kD。这一片段能够移行入胞核，结合于SRE-1，从而激活LDLR基因翻译和HMGCoA合酶基因翻译。 SREBPs裂解、移行入胞核，进而结合于SRE-1，以致激活LDLR基因、HMGCoA合酶基因，都有赖于细胞内缺乏胆固醇。因为胆固醇能够抑制SREBPs的裂解。而已形成的SREBPs的裂解片段又很容易被迅速分解，从细胞核中快速消失。故而胆固醇的存在，将阻断整个调节通路，使SRE-1失活。
将SREBP-1和SREBP-2进行cDNAg隆，并采用质粒转染动物细胞的方法，使培养细胞，如Hela细胞和中国仓鼠卵巢细胞（CHO细胞），表达SREBP-1和SREBP-2，发现他们调节细胞内胆固醇代谢的过程是一致的，功能上是协同的，然而两种蛋白质是单独发生作用，没有发现杂化二聚体。为什么存在这两种组成不同但功能一致的SREBPs，原因还不清楚。
研究仓鼠肝脏中产生的，由细胞内胆固醇含量调节的mRNA（包括LDLR和HMGCoA合酶的mRNA）的含量。肝脏经HMGCoA还原酶抑制物mevinolin处理后，这两种mRNA的量都增加。通过阻止胆固醇的合成，mevinolin诱导暂时的胆固醇水平降低，而增强胆固醇调节基因的翻译。当mevinolin和胆汁酸结合树酯，如降胆灵合用时，mevinolin增强翻译的效果更强。降胆宁通过阻止肠道对胆汁酸的再吸收，使胆固醇转变为胆汁酸，因而增加肝脏对胆固醇的进一步需求。
最近，研究HMGCoA还原酶抑制物和胆汁酸结合树酯是否促进SREBP-1和SREBP-2在仓鼠肝脏中的蛋白裂解，与在培养的细胞中的发现有些不同。资料表明SREBP-1和SREBP-2的裂解片段在仓鼠肝脏中的调节作用是不一致的。仓鼠肝脏经mevinolin
加降胆宁处理后，SREBP-2的裂解片段增多，而SREBP-1的裂解片段减少。这一结果似乎表明在仓鼠肝脏中，SREBP-1对LDLR和HMGCoA合酶基因的基础翻译起作用，而SREBP-2对经胆汁酸结合树酯和胆固醇还原酶抑制物处理后，形成的胆固醇缺乏状态的基因翻译起作用。
另有报道，胰岛素和类胰岛素生长因子Ⅰ也可以通过SREBP-1介导LDL-R启动子的激活，从而调节细胞内的胆固醇含量。
总之，在细胞内胆固醇含量的自我平衡中，SREBPs起了重要作用，其详细机制的阐明，必然对胆固醇代谢调节的研究产生重大影响。
（董学梅 滕思勇
郑 芳
崔天盆）
参 考 文
1.Drayna D,Jarnagin A,Mclean J,et al Colnning and sequencing of human cholesteryl ester transfer protein cDna,Narure,1987,327:632-634
2.Abbey M.Savage J,Mackimnnon A,et al .Detection of lipid transfer protein activity in rabbit perfusate.Biochim Biophys Acta,1984,793:481-484
3.Nishida H,Katolt,Nishida T.Affinty of lipid transfer protein for lipid and lipoprotein particles as infuenced by lecithine cholesteryl acyltransferase.J Biol Chem,1990,265:4876-4883
4.Tall A.Plasma lipid transfer proteins .Jlipid Res ,1986<27:361-367
5.Hussain M,Maxfield F,Mas Olira J,et al .Clearance of chylomicron remnants by the low denisty lipoprotein receptor-related.J Biol Chem,1991,266:13936-13940
6.Scottrup Jenesen L Alpha-Macroglobulins:structure,shape and mechansim of proteinase complesx formation. J Biol Chem,1989,264:11536-11542
7.Strickland D,Ashcom J,Williams S,et al Sequence identity between the α2-Macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor ,J Biol Chem,1990,265:17401-17404
8.Brown M,Goldstein J,et al .A receptor mediated pathway for cholesterol homeostasis .Science,1986,232:34-47.
9.Smith J R,Oshrne T F,Goldstein J L,et al Identification of nucleotides responsible for enhancer activity of sterol regulatory element in LDLR gene.J Biol Chem,1990,265:2306-2310
10.Briggs M R,Yokoyama C,Wang X,et al .Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promotor.J Biol Chem,1990,265:14490-14496
11. Youkoyama C,Wang X,Bringgs M R,et al ,srebp-1,a basic-helix-loop-helix-leucine zipper proteins that controls transcription of the low density lipoprotein receptor gene Cell,1993,75:187-197
12.Goldstein JL ,Brown M S.Regulation of the mevalonate pathway .Natute,1990,343:425-430
13.Rajavashioth T B,Taylor A.K,Andalibi A,et al
.Identification of a zinc finger protein that binds to the sterol regulatory element .Science,1989,245:640-643
14.Wang X,Briggs M R,Hus X,et al. Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter.J.Biol
.Chem,1993,268:14497-14504
15. Kadesch T,Consequences of heteromeric interactions among helix-loop-helix protein.Cell Growth Differ.1993,4:49-55
16.Beckman H,Sul K,kadesch T.TFE3:a helix-loop-helix protein that activated transcription through the immunoglobulin enhancer motif .Gene.KEV.1990,4:167-179
17.Hua X,Yokoyama C,WuJ,et al.SREBP-2,a second basic-helix-loop-helix-leucine zipper protein that stimulates transcription by binding to a sterol regulatory element Proc Natl Acad Sci USA,1993,90:11603-11607
18.Sato R,Yang J,Wang X,et al.Assignment of the membrane attachment ,DNA bindings ,and transcriptional activation domains of sterol regulatory element-binding protein-1(SREBP-1).J Biol Chem,1994,269:17267-17273
19.Wang X,Sato R,Brown M S,et al SREBP-1,a membrane-bound transcription factor released by sterol-regulated proteolysis ,Cell,1994,77:53-62
20.Ma PTS,Gil G,Sudhof T C,et al .Mevinolin,an inhibitor of cholesterol sythesis induces Mrna for LDLDR in livers of hasmters and rabbits .Proc Natl Acad Sci USA,1986,83:8370-8374
21.Mehrabian M,Callaway K A,Clarke C F,et al Regulation of rat liver 3-hydroxy-3-methsutaryl coenzyme A synthase and the chromosomol localization of the humen gene J Biol Chem,1986,261:16249-16255
22.Brown M S,Goldstein J L.A receptor mediated pathway for cholesterol homeostasis .Science,1986,232:34-47
23.Sherg Z,Otani H,Brown M S,et al.Independent regulation of sterol regulatory element-binding protein 1 and 2 in hasmster liver.Prot Natl Acad Sci USA,1995,92:935-938
24.Streicher R,Kotzka J,Muller-Wieland D,et al
.SREBP-1mediates activation of the low density lipoprotein receptor promoter by insulin and insulin-like growth factor-I.J Biol Chem;1996,7128-7133
25.Wetterau J R,Zilversmit D B.Atriglyceride and cholesteryl ester transfer protein associated with liver microsomes .J,Biol Chem,1984,259(17):10863-10886
26.Wetterau J R,Aggerbect,L P,Laplud M L ,et al .Structural properties of the microsomal triglyceride transfer rpotein complex.Biochemistry.1991,30(18):4406-4412
27.Wetterau J R,Combs K A.Snipnner S N,et al .Protein disulfide isomerase is a component of the microsomal triglyceride transfer protein complex.J Biol Chem,1990,265(17):9800-9807
28.Goldberger R F,Epstein C J,Acceleration of reactivation of reduced bovine pancreatic ribonuclease by a microsomal system from rat Liver J Biol Chem,1963,238:628-635
29.Sharp D,Ricci B Kicnzle B Kienzle B,et al Human microsomal triglyceride transfer protein large subunit gene structure, Biodomistry ,1994,33(31):9057-9061
30.Sharp D,Blindeman L.Combs K A et al .Cloning and gene defects in microsomal triglyceride transfer protein associated wiyth abetalipoproteinaemia Nature ,1993,258:999-1001
31.Mathur S N,Born E,Marygy S,et al .Microsomal triglyceride transfer protein in CaCo-2 Cell:characterization and regulation .J Lipid Res,1997,38(1);61-67
32. Weterau J R,Aggerbert LP.Bouma ME ,et al Absence of microsomal triglycetride transfer protein in individuals with abetalipoproteinaemia Science,1992,258:999-1001
33.Wetterau J R,Combs K A,Mclean LR ,et al .Protein disulfide isomnerase appears necessary to maintain the catalytically active structure of the microsomal triglyceride transfer protein .Biochemistry,1991,30(40):9728-9735
34.Ricci B,Shrp D.Rourke E,et al .A30-amino acid truncation of the microsomal triglyceride transfer proteinlarge subunit disrupts its interaction with protein disulfide-isomerase and causes abetalipoproteinaemia.J,Biol.Chem,1995,270(24):14281-14285
35.Wetterau J R,Lin M,Jamil H.Microsomal triglyceride transfer protein Biochim Biophy Acta ,1997,1345(1);136-150
36.Boren J,Rustaeus S,Olofsson S.O.Studies on the assembly of apolipprotein B-48 containing verylow density lipoproteins in MCARH7777 cells,J Biol Chem,1994,(269(41)25879-25888
37.Atael A.Wetterau J R.Mechansim of microsomcl triglyceride transfer protein catalyzed lipid transport.Biochemistry,1993 ,32(39);10444-10450
38.Sniderman A,et al .Alseuce of microsomal triglyceride transfer protein in indeviduals with abetalipoproteinemia.
39.Shrp D,Blinderma L,Combs K,et al.Cloning and gene defects in microsomal triglyeride transfer protein associated with abetalipoproteinemia Nature ,1993,365:65
40.Sniderman A S,Marpole D M,Sdinner B,Kwiviterovich ,et al. The saaociaton of coronary atherosclerosis cholesterol content in human plasma low density lipoprotein .Prot Nat Acad Sci USA,1990,97:604-608
41.Sniderman A S,Marpole D M.Skinner B,Kwivterovich ,et al.The association of coronary atherosclerosis cholesterol content in human plasma low density lipoprtein .Prot Natl Acad Sci USR ,1990,97:604-608
42.Teng B,Thompson GR,Smiderman AD,et al.Composition and distrbution of low density lipoprotein fracteons in hyperapobetalipoproteinemia ,normolipidemia and familial hypercholesteroemia Prot Natl Acad Sci USA ,1983,80:6662-6666
43.Kwiterovich Po Jr,white S,Forte T,et al.Hyperapobetalipoproteinemia in a kinderd with familial combined hyperlipidemica and familial hypercholeserolemia .Arteroscler Thromb,1987,7:211-225
44.Kwiterovich Po Jr,Coresh J Bachorik PL Prevalence of hyperapobetalipopproteinemia and other lipoprotein phenotypes in men(≤50years
)and women(≤60years)with coronary disease Am J Cardiol,1993,71:631-639
45.Brunzdll JD.Sniderman AD,Albers JJ,et al.Apolipoprotein B and coronary artery disease in humans.Arterioscler Thromb,1984,4:79-83
46.Kwiterovich po Jr.HyperAopB:a pleiotrothic phenotype characterized by dense low density liporoteins and associated with coronary artery disease.Clin Chem,1988:34(supple B-1-B-135)B71-B83
47.Cianflone K,Kwiterovich po Jr,Wslsh M,et al.Stimulation of fatty acid uptake and triglyceride synthesis in human cultured sdin fibroblasts and adipocytes by a serum protein.Biohys Res commun,1987,144:94-100
48.Cianflone KM,Rodriguez MA,Welsh MJ,et al.Effect of acylation-stimulation protein on triglyceride synthesis in cultured skin fibroblasts from normals and patients with hyperapobetalipoproteinemia(Abstract)Arteriosclerosis,1987,7:496
49.Cianflone KM,Rodriguez MA,Walsh M,et al.Purification and characterization of caylation-stmulating protein,J Biol Chem,1987,7:496
50.Kwiterovich Po Jr,Motevlli M,Miller M Acylation stimulating activity in hyperapobetalipoproteinemia fibrolasts enhanced cholesterol esterification with another serum basic protein BPⅡ.Proc Natl Acad Sci USA,1990,87:8980-8994
51.Vahouny GV,chanderbhan R,kharroabi A.Sterol carrier and lipid transfer protein (Revicw).Adv Lipid Res,1987,22:83-113
52.Kwiterovich PO,Jr,Motevalli M,Miller M.The effect of three serum basic proteins on the mass of lipids in normal and hyperAopB fibroblasts Arterioscler Thromb,1994,14:1-7
53.Teng BA,Forse MA,Rodriguez AD,et al.Adipose tissue glyceride synthesis in patients eith hyper aplbetalipoprotenemia J Physiol Pharmacol,1988,66:239-242
54.Cianflone KM,Maslowska MH.Sniderman AD.Impaired response of fibroblasts from patients with hyperapobeta lipoproteinemia to acylation-stimulating protein.Jclin Invest.,1990,85:722-30
55.Babirak SP.Iverius PH,Fujimoto WY.Detection and characterization of the heteroazygous state for lipoprtein lipase deficiency ,Arteriosclenosis
.1989,9:326-34
56.Kwiterovich PO.Jr,Motevalli M,Miller M,The effect of three serum basic proteins on the mass of lipid in normal and hyperapoB fibroblasts .Arterioscler Thromb,1994,141-7
57. Baldo AD.Sniderman S Kohen MK,Cianflone signal transduction pathway of acylation stimulating protein involvement of protein kinase C.J lipid Res 1995,36:1415-1426
58.Kwiterovich PO Jr ,Motevalli Miller M,Inhibition of protein tyrosine dinase alters the effcet of serum basic protein I on tracylglycerol and cholesterol differently in normal and hyperapoB fibroblasts Arteriolcler Thromb Vasc Biol,1995,15:1195-1203
59.Castagna MY,Takai KK,et al .Direct activation of calcium activated phospholipid dependent protein dinase by tumor promoting phorbol esters J Biol Chem,1982,257:7847-7851
60.Witters L A,and PJ,Blackshear,Protein kinase C mediated phosphorylation in intact cells Methods Enzymol1987,141:412-425
61.Etscheid BG,Albert KA,Villereal ML,et al.Transduction of the bradykinin response in human fibroblasts prolonged elevation of diacyglycerol level and its correlation cell.Reg .1991,3:229-239
62.Zor VE,Her T,Harell G.et al.Arachidonic acid release bybasophilic leudemia cells and macrophages stimulated by Ca2+ ionophores,antigen and diacylglycerol:essential role for protein dinase C and prevention byglucocorticosteroids.Biochem Biophys Acta.1990,1091:385-392
63.Ishizuda TJ,Hoffman DR,Cooper JE,et al.Clucose induced synthesis of ciacylglycerol de novo is associated with translocation cactivation of protein kinase C in rat adipocytes FEBS Lett.1989,249:234-238
64.Sato R.Goldstein JL,Browm MS,Replacement of serine871 of hamster 3-hydroxy-3methylglutaryl coA reductase prevents phosphorylation by a AMP-activated kinase and blocks inhibition of sterol synthesis indrced by ATP depletion Proc Natl Acad Sci USA,1993,90:9261-9265
65.Bolen JB,Non erceptor tyrosine protein kinases Oncogene.1993,8:2025-2031
66.Park DJ.Nin HK,Rhee SG,IgE-in duced tyrosine phosphorylation of phospholipase Cr-1 in rat basophilic leukemia cells J.Biol Chem,1991,266:24237-24240
67.Cianflone K,AD Sniderman M.J.Walsh.H.et al.Purification and characterization of acylation stimulating protein .J.Biol Chem,1989,264:426-430
68.Germinario R,A Sniderman D Manuels S.et al .Coordinate response of triacylglycerol synthesis and glucose transport by acylation stimulating protein ,Metab Clin Exp.1993,42:574-580
69.Yasruel Z,Cianflinge K,Sniderman AD,et al.Effect of caylation stimulating protein on the triacylglycerol synthetic pathway of human adipose tissue .Lipids .1991,26:495-499
70.Mayorek No,I Grinstein and J.Bar Tana.Triacylglycerol
.synthesis in cultured rat hepatocytes EurJ Biochem,1989,182:395-400
71.Teng B.Sniderman AD.Soutar AK,et al. Metabolic basis of hyperapobetalipoproteinemia J Clin Invest .1986,77:663-672
72.Cook KS,Min D,Fnhnson et al.Adipsin:a circulating serine protease homolog secreted by adipose tissue and sciatic nerve.Science(Wash.DC).1987,237:402-405
73.White RT.Damon .N,Hancodk ,et al.Human adipoin is identical to complement factor D and is expressed at high levels in adipose tissue.J Biol Chem,1992,267:9210-9213
74.Choy LN,Rosen BS.B.M Spiegelman.Adipsln and an endogenous pathway of complement from adipose cells,J Biol Chem,1992,267:12736-12741
75.Cianflone KA,Snielerman D.Walsh MJ,et al .Adipsin/Acylatin stimulating protein system in human adipocytes :regulation of triacylglycerol synthesis.Bioxhemistry.1994,33:9489-9495
76.Spiegelman BM,Fraik M,Green,H,Molecular cloning of mRNA from 3T3 adipocytes J Biol Chem,258,16:10083-10089
77.Cook KS,Groves ,DL,Min HY,et al.A devlopmently regulated mRNA from 3T3 adipo cytes cncodes A novel serine protease homologue .Proc Natl Acad Sci USA.1985,82:6480-6484
78.Sniderman A.Shapiros ,Marpole D,et al. Association of coronary atheroscleros is with Ah perapo beta lipoprotenemia .Proc Natl Acad Sci USA,1980,97:604-608
79.Sniderman A.Wolfson V,Teng B.Association of hyperaobetalipwproteinemia with endogenous hypertrglyceridemia and atherosclerosis Bachorikp Ann Intern Med .1982,97:833-839
80.Teng B Thompson GR Sniderman AD,Composition and distrbution of low ednsity lipoprotein fractions in hyperapobetalipoproteinemia normolpidemia ,and familial hypercholesterolemia .Proc Natl Acad Sci USA
1983,80:6662-6666
81. Flier JS,Cook KS,Vsher P,et al.Severely Iimpaired adipsin expression in genetic and acquired obesity ,Science .1987,244:1483-1487
82.Rosen BS,Cook KS,Yaglom Jet al .Adipsin and Comlement factor D activity:an immune-pelated defect in obesity .Science ,1989,244:1483-1487
83.Dovis RA,Boogaerts JR.Intranepatic assembly of very low density lipoproteins J Biol chem,1982,257:10908-10913
84.Hugli TE.Biochemistry and biology of anaphylatoxin curr topics microbiol immunol ,1989,153:181-208
85.Praz F.Rauth EJ.Growth-supporting activity of fragment ba of the human alternative complement pathway for activated murine B lymphocytes
.J Exp Med 1986,163,1349-1354
86.Ambrus JL,Jr Peters MG,Fauci AS,et al.The ba fragment of xomplement factor B Inhibits human Blymphocyte proliferation J Immunol
.1990,144:1549-1533
87.Campeau L Enjabert M.lesperange J et al .The pelation of risk factors to the development of atheroscerosis in saphenous-vein bypass corafts and the progression of disease in the native circulation N Engl J Med
.1984,311:1329-1332
88.Brown BO,Alberts JJ,Fisher LD,et al.Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B.N Engl J Med,1990,319:1289-1298
89.Kwiterovich PO,Ir.whitxy ,Forte Tet al.Hyperapobetalipoproteinemia in a dindred with familial combined hyperlipidemia and rfmilial hypercholesterolemia Artriosclerosis,1987,7:211-225
90.Sandkamp M,Funke H.Schulte H,K liporotein (a)Is An Iadependent risk tactor for myocardial in farction at Yong are ,Clin Chem,1990,36:20-6
91.ladias JA,K witerovich PO,Ir,Smith H,et al.A missense mutation arinine 4019-tryptophan in apolipoprotein B in a famliy with hyperapoB and premature atherosclerosis .Arteriosclersis ,1987,7:492
92.Gavish D,Brinton EA,Breslow JL,Heritable allele –specisic differences in amounts of apoB,and low-density lipoproteins in plasma.Science.1989,244:72-76
93.Coresh J,Kwiterovich PO,Jr,Antoaradis SE,HyperapoB a pleiotropic phenotype cheracterized by dende lowdendity lipoproteins and associated with coronary diseade .Am J Hum Genet ,1990,47(3):A130
94.Teng B.Sniderman AD,Krauss RM,Modulation of apolipoprotein B antigenic determinants in human low density lipoprtein subclasses J Biol chem,1985,260;5067-5072
95.Knighy BL,Thompson GR,Soutar AK.Binding and degradation of heavy and lighy subfractions of low density lipoprotein by cultured fibroblasts and macrophages Atherosclerosis.1986,59:301-306.
96.White R T, Damm D.Hanxock N.et al. Cell Biol.1991 in press., 百拇医药