Increased cholesterol biosynthesis and hypercholesterolemia in mice overexpressing squalene synthase in the liver
Increased cholesterol biosynthesis and hypercholesterolemia in mice overexpressing squalene synthase in the liver
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DOI：
10.1194/jlr.m600224-jlr200
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发表时间：
2006-09-01
影响因子：
6.5
通讯作者：
Ishibashi, Shun
中科院分区：
文献类型：
--
作者：
Okazaki, Hiroaki;Tazoe, Fumiko;Ishibashi, Shun
角鲨烯合酶（SS）是胆固醇生物合成的第一个关键酶，位于甲羟戊酸途径的一个分支点。为了研究SS在整体胆固醇代谢中的作用，我们使用腺病毒介导的基因转移在小鼠肝脏中瞬时过表达小鼠SS。SS的过表达增加从头胆固醇的生物合成与增加3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶活性，尽管其自身的mRNA表达下调。此外，SS的过度表达增加了血浆中LDL的浓度，无论是否存在功能性LDL受体（LDLR）。因此，高胆固醇血症主要是由富含胆固醇的VLDL的肝脏产生增加引起的，如通过静脉内注射Triton WR 1339后血浆胆固醇水平的增加所证明的。低密度脂蛋白受体的mRNA表达降低，这表明有缺陷的低密度脂蛋白清除有助于高胆固醇血症的发展。奇怪的是，肝脏变大，Ki-67阳性细胞数量增多。这些结果表明，SS的瞬时上调刺激胆固醇的生物合成以及脂蛋白的产生，提供了第一个体内证据表明，SS通过调节HMG-CoA还原酶活性和胆固醇的生物合成在胆固醇代谢中起着调节作用。
Squalene synthase (SS) is the first committed enzyme for cholesterol biosynthesis, located at a branch point in the mevalonate pathway. To examine the role of SS in the overall cholesterol metabolism, we transiently over-expressed mouse SS in the livers of mice using adenovirus-mediated gene transfer. Overexpression of SS increased de novo cholesterol biosynthesis with increased 3-hydroxy-3-methyglutaryl-CoA (HMG-CoA) reductase activity, in spite of the downregulation of its own mRNA expression. Furthermore, overexpression of SS increased plasma concentrations of LDL, irrespective of the presence of functional LDL receptor (LDLR). Thus, the hypercholesterolemia is primarily caused by increased hepatic production of cholesterol-rich VLDL, as demonstrated by the increases in plasma cholesterol levels after intravenous injection of Triton WR1339. mRNA expression of LDLR was decreased, suggesting that defective LDL clearance contributed to the development of hypercholesterolemia. Curiously, the liver was enlarged, with a larger number of Ki-67-positive cells. These results demonstrate that transient upregulation of SS stimulates cholesterol biosynthesis as well as lipoprotein production, providing the first in vivo evidence that SS plays a regulatory role in cholesterol metabolism through modulation of HMG-CoA reductase activity and cholesterol biosynthesis.