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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)

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