Faust J R, Goldstein J L, Brown M S
Proc Natl Acad Sci U S A. 1979 Oct;76(10):5018-22. doi: 10.1073/pnas.76.10.5018.
Squalene synthetase (farnesyltransferase; farnesyl diphosphate:farnesyl-diphosphate farnesyltransferase, EC 2.5.1.21), the enzyme in the cholesterol biosynthetic pathway that converts farnesyl pyrophosphate into squalene, is subject to regulation in cultured human fibroblasts. When cholesterol-carrying low density lipoprotein (LDL) was removed from the serum of the culture medium, squalene synthetase activity increased 8-fold over 24 hr. When LDL was added back to the medium, squalene synthetase was slowly suppressed, 50% and 90% reduction occurring in 15 and 48 hr, respectively. Suppression of squalene synthetase required uptake of LDL via the LDL receptor; hence, it did not occur in mutant fibroblasts from a patient with homozygous familial hypercholesterolemia that lack receptors. The addition of a mixture of 25-hydroxycholesterol and cholesterol suppressed squalene synthetase equally well in normal and mutant fibroblasts. Coupled with previous data, the current findings indicate that cholesterol derived from LDL regulates at least two enzymes in the cholesterol synthetic pathway in fibroblasts: (i) its primary action is to rapidly suppress 3-hydroxy-3-methylglutaryl coenzyme A reductase [mevalonate:NADP(+), oxidoreductase (CoA-acylating), EC 1.1.1.34], which reduces mevalonate production by 95% within 8 hr, and (ii) its secondary action is to slowly suppress squalene synthetase. The LDL-mediated suppression of squalene synthetase does not regulate de novo cholesterol synthesis; it occurs after 3-hydroxy-3-methylglutaryl coenzyme A reductase is already suppressed. Rather, we hypothesize that it may function to allow the pool size of farnesyl pyrophosphate to be maintained in the presence of LDL so that low levels of mevalonate can be shunted preferentially into nonsterol products, such as ubiquinone-10 and dolichol. This mechanism may explain the earlier observation that the synthesis of ubiquinone-10 in fibroblasts proceeds at a normal rate in the presence of LDL despite a 95% decrease in mevalonate production.
角鲨烯合成酶（法尼基转移酶；法尼基二磷酸：法尼基二磷酸法尼基转移酶，EC 2.5.1.21）是胆固醇生物合成途径中一种将法尼基焦磷酸转化为角鲨烯的酶，在培养的人成纤维细胞中受到调控。当从培养基血清中去除携带胆固醇的低密度脂蛋白（LDL）时，角鲨烯合成酶活性在24小时内增加了8倍。当将LDL重新添加到培养基中时，角鲨烯合成酶被缓慢抑制，分别在15小时和48小时内抑制50%和90%。角鲨烯合成酶的抑制需要通过LDL受体摄取LDL；因此，在缺乏受体的纯合子家族性高胆固醇血症患者的突变成纤维细胞中不会发生这种情况。添加25-羟基胆固醇和胆固醇的混合物在正常和突变成纤维细胞中对角鲨烯合成酶的抑制效果相同。结合先前的数据，目前的研究结果表明，源自LDL的胆固醇调节成纤维细胞胆固醇合成途径中的至少两种酶：（i）其主要作用是迅速抑制3-羟基-3-甲基戊二酰辅酶A还原酶[甲羟戊酸：NADP(+)，氧化还原酶（辅酶A酰化），EC 1.1.1.34]，该酶在8小时内将甲羟戊酸的产生减少95%，（ii）其次要作用是缓慢抑制角鲨烯合成酶。LDL介导的角鲨烯合成酶抑制并不调节从头合成胆固醇；它发生在3-羟基-3-甲基戊二酰辅酶A还原酶已经被抑制之后。相反，我们假设它可能起到在存在LDL的情况下维持法尼基焦磷酸库大小的作用，以便低水平的甲羟戊酸能够优先分流到非甾醇产物中，如泛醌-10和多萜醇。这一机制可能解释了早期的观察结果，即尽管甲羟戊酸的产生减少了95%，但在存在LDL的情况下，成纤维细胞中泛醌-10的合成仍以正常速率进行。
