HMGCoA還原酶(HMGCoa reductase)是膽固醇合成的限速酶，存在于小胞體膜，催化合成甲基二羥戊酸(mevalonic acid)，并生成體內(nèi)多種代謝產(chǎn)物，稱之為甲基二羥戊酸途徑。細胞內(nèi)膽固醇水平調(diào)節(jié)主要信賴于內(nèi)因性膽固醇合成途徑和LDL受體攝取細胞外膽固醇的外因途徑兩條。Goldstein ,Brown闡明其抑制機制認為，細胞內(nèi)ch作為HMGCoA還原酶抑制劑使其活性降低，肝細胞膜上的LDL受體增加，從血中攝取ch增加，使血中膽固醇水平降低，設想HMGCoA還原酶活性降低的藥物可使血中膽固醇水平下降，尤其是對FH的雜合子患者，LDL受體數(shù)銳減者可起治療作用。
Kovanen等報導以merinolin的HMGCoA還原酶抑制劑投入，使狗血中LDL消失速度上升，LDL產(chǎn)生速度下降，肝移植的小兒FH純合子患者，用梅維諾林治療可使LDL膽固醇降低40%，而LDL產(chǎn)生速度下降35%，LDL合成減少的機制，有兩種可能，一是膽固醇合成減少使VLDL生成量降低；第二是HMGCoA還原酶抑制劑使VLDL殘�；颚耉LDL異化增加，轉(zhuǎn)變成LDL減少，體外實驗也證實，從VLDL殘粒到LDL的速度比正常狀態(tài)下小20倍，與此同時LDL受體的親和力也增加。
倉鼠HMGCoA還原酶基因長30kb，由20個外顯子組成，在啟動子5'端富含GC堿基。HMGCoA還原酶，從轉(zhuǎn)錄水平作為膽固醇代謝的調(diào)節(jié)點，與LDL受體基因啟動子，HMGCoA合成酶，從轉(zhuǎn)錄調(diào)節(jié)域存在有相同的堿基系列，即CACCCC(或GT)AC的膽固醇調(diào)節(jié)元件(sterol regulatory element,SRE)存在，如圖5-5所示。
圖5-5 膽固醇代謝調(diào)節(jié)的啟動子與SRE
第一條線的數(shù)字為從轉(zhuǎn)錄開始的距離(堿基對數(shù))
(董學梅)
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