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第四节 Hmgcoa还原酶
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HMGCoA还原酶(HMGCoa reductase)是胆固醇合成的限速酶,存在于小胞体膜,催化合成甲基二羟戊酸(mevalonic acid),并生成体内多种代谢产物,称之为甲基二羟戊酸途径。细胞内胆固醇水平调节主要信赖于内因性胆固醇合成途径和LDL受体摄取细胞外胆固醇的外因途径两条。Goldstein ,Brown阐明其抑制机制认为,细胞内ch作为HMGCoA还原酶抑制剂使其活性降低,肝细胞膜上的LDL受体增加,从血中摄取ch增加,使血中胆固醇水平降低,设想HMGCoA还原酶活性降低的药物可使血中胆固醇水平下降,尤其是对FH的杂合子患者,LDL受体数锐减者可起治疗作用。

Kovanen等报导以merinolin的HMGCoA还原酶抑制剂投入,使狗血中LDL消失速度上升,LDL产生速度下降,肝移植的小儿FH纯合子患者,用梅维诺林治疗可使LDL胆固醇降低40%,而LDL产生速度下降35%,LDL合成减少的机制,有两种可能,一是胆固醇合成减少使VLDL生成量降低;第二是HMGCoA还原酶抑制剂使VLDL残粒或βVLDL异化增加,转变成LDL减少,体外实验也证实,从VLDL残粒到LDL的速度比正常状态下小20倍,与此同时LDL受体的亲和力也增加。

仓鼠HMGCoA还原酶基因长30kb,由20个外显子组成,在启动子5'端富含GC碱基。HMGCoA还原酶,从转录水平作为胆固醇代谢的调节点,与LDL受体基因启动子,HMGCoA合成酶,从转录调节域存在有相同的碱基系列,即CACCCC(或GT)AC的胆固醇调节元件(sterol regulatory element,SRE)存在,如图5-5所示。

图5-5 胆固醇代谢调节的启动子与SRE

第一条线的数字为从转录开始的距离(碱基对数)

(董学梅)

参 考 文 献

1.杨振华,酶的测定,见:叶应妩,李健斋,王玉琛主编。临床实验诊断学,北京:人民卫生出版社,1991,588~466

2.Paltarf F,Wagner E,Stereospecificity of Lipase enzymatic hydrolyosis of enantiomeric aldyldiacyl and dialdylacylglyerols by lipoprotein lipase.Biochim Biophys Acta,1976,431:359-362

3.Deeb SS.Peng R.Structure of the human lipoprotein lipase gene .Biochemistry,1989,1169:582-4134

4.Gotoda T,et al.Anewly identified null allelic mutation in the human lipoprotein lipase(LPL)gene of a compornd heterozygote with familial LPL deficienacy,Biochys Acta,1992,1169:582-586

5.Okabe T,Yorifaji H,et al .Pulmonary macrophage:Amajor source of lipoprtein lipase in the lung.Biochim Biophys Res Commun,1984,125:273-278

6.Oka K,George T,Stocks J,et al.Nucleotide sequence of PvuⅡpoolymorphic site at the human lipoprotein lipase gene locus .Nuceic Acids Research,1990,18:5407-5411

7.Chuat J,Raisonnier A,Etienne J,et al.The lipoprotein lipase-encodigng human gene:sequence from intron-6 to intron-9 and presence in intron-7 of a 40-million-year-old Alu sequence.Gene,1992,110:257-261

8.Gotoda T,Yamada N,Murase T,et al .Detection of three separate DNA polymorphisms in the human lipoprotein lipase gene by gene amplfication and restriction endonuclease digestion.J Lipid Res,1992,33:1067-1072

9.Raj K,Edward W,Ruth M,et al .DNA variants at the LPLgene locus associate with angiographically defined severity of atherosclerosis and serum lipoprotein levels in a welsh poprlation.Arteriosclerosis and Thrombosis,1994,14:1090-1097

10.Robert A,Andrew J,Liling T,et al .Agene-gender interaction affecting plasma lipoproteins in a genetic isoalate,Arteriosclerosis and Thrombosis,1994,14671-677

11.Yang C,et al.Lecithin:cholesterol acyltransferase.J Biol Chem,1987,262:3086-3091

12. Alberts J,Adolphson J,Chen C,et al.Radiommunoassay of human plasma lecithin cholesterol acyltransferase.J Clin Invest,1981,67:141-148

13.Mclean J et al .Cloning and expression of human lecithin cholesterol transferase cDNA ,Proc Natl Acad Sci USA ,1986,83:2335-2339

14.Glomset .J.Norum K,Gjone E,et al.Lecithin:cholesterol acyltransferase deficiency.In:The Metabolic Basis of Inherited Disease.McGraw Hill ,New Youk,1983,643-654

15.Glomset J.The plama lecithin cholesterol acyltransferase reaction.J Lipid Res,1968,9:156-167

16.Holmqusit Z,Carlson L.Normalization of high density lipoprotein in fish eye disease plasma by purified normal human lecithin cholesterol acyltransferase .Lipids ,1988,23:225-229

17.Zilversmit D B.Atherogenic nature of triglycerides .postprandial lipidemia and triglyceride-rich remnant.Clin Chem,1995,41:153-158

18.Takagi A, et al.Molecular strdies on primary lipoprotein lipase(LPL)deficiency:one base deltion (G916)in exon 5 of LPL gene causes no detectable LPL protein due to the absence of LPLmessenger RNA transcript.Jclin Invest,1992,41:153-158

19.Jingami R,Brown M,Goldstein J,et al .Partial deletion of membrane-bound domain of 3-hydroxy-3methylglu-taryl coenzyme a reductase eliminates sterol enhanced degradation and prevents formation of crystalloid endoplasmic reticulum,Jcell Biol,1987,104:1693

20.Goldsteir J,Brown M,Regulation of the mevalonate pathway.Nature ,1990,343:425-430

21.East C,Grundy S,Bilheimer D,et al.Preliminary report:Treatment of ytpe 3 hyperlipidemia with mevinolin.Metabolism,1986,35:97098-,104:1693

22.阵上久人,HMGCoa Reductaseとそのinhibiter .最新医学,1992,47:82-90