第四节 HMGCoA还原酶
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)
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