Activation of cholesterol synthesis in preference to fatty acid synthesis in liver and adipose tissue of transgenic mice overproducing sterol regulatory element-binding protein-2
Activation of cholesterol synthesis in preference to fatty acid synthesis in liver and adipose tissue of transgenic mice overproducing sterol regulatory element-binding protein-2
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DOI：
10.1172/jci2961
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发表时间：
1998-06-01
影响因子：
15.9
通讯作者：
Shimano, H
中科院分区：
文献类型：
--
作者：
Horton, JD;Shimomura, I;Shimano, H
我们生产的转基因小鼠，表达显性阳性截短形式的固醇调节元件结合蛋白-2（SREBP-2）在肝脏和脂肪组织。编码的蛋白质缺乏膜结合和COOH末端调节结构域，因此不易受胆固醇的负调节。来自转基因小鼠的肝脏显示出编码胆固醇生物合成、LDL受体和脂肪酸生物合成的多种酶的mRNA的增加，3-羟基-3-甲基戊二酰辅酶A（HMG CoA）合成酶和HMG CoA还原酶的mRNA升高尤其显著（分别为13倍和75倍）。结果，通过腹腔注射[H-3]水测量，转基因肝脏显示胆固醇合成速率增加28倍，脂肪酸合成增加不到4倍。这些结果与先前报道的显性阳性SREBP-1a的作用形成对比，SREBP-1a激活脂肪酸合成多于胆固醇合成。在SREBP-2转基因动物的脂肪组织中，胆固醇生物合成酶的mRNA升高，但脂肪酸生物合成酶的mRNA没有升高。我们的结论是，SREBP-2是一个相对选择性的激活剂的胆固醇合成，而不是脂肪酸的合成，在肝脏和脂肪组织的小鼠。
We produced transgenic mice that express a dominant-positive truncated form of sterol regulatory element-binding protein-2 (SREBP-2) in liver and adipose tissue. The encoded protein lacks the membrane-binding and COOH-terminal regulatory domains, and it is therefore not susceptible to negative regulation by cholesterol, Livers from the transgenic mice showed increases in mRNAs encoding multiple enzymes of cholesterol biosynthesis, the LDL receptor, and fatty acid biosynthesis, The elevations in mRNA for 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) synthase and HMG CoA reductase were especially marked (13-fold and 75-fold, respectively). As a result, the transgenic livers showed a 28-fold increase in the rate of cholesterol synthesis and a lesser fourfold increase in fatty acid synthesis, as measured by intraperitoneal injection of [H-3]water. These results contrast with previously reported effects of dominant-positive SREBP-1a, which activated fatty acid synthesis more than cholesterol synthesis. In adipose tissue of the SREBP-2 transgenics, the mRNAs for cholesterol biosynthetic enzymes were elevated, but the mRNAs for fatty acid biosynthetic enzymes were not. We conclude that SREBP-2 is a relatively selective activator of cholesterol synthesis, as opposed to fatty acid synthesis, in liver and adipose tissue of mice.