Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells
Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells
复制标题
DOI：
10.1172/jci119248
复制
发表时间：
1997-03-01
影响因子：
15.9
通讯作者：
Goldstein, JL
中科院分区：
文献类型：
--
作者：
Shimano, H;Horton, JD;Goldstein, JL
我们已经培育出肝脏表达甾醇调节元件结合蛋白1c （SREBP-1c）显性nh2端阳性片段的转基因小鼠。与全长SREBP-1c不同，nh2末端片段进入细胞核不需要从细胞膜上蛋白水解释放，因此它不受甾醇的下调。我们将SREBP-1c转基因小鼠与产生等量SREBP-1a nh2末端片段的转基因小鼠进行了比较。SREBP-1a和-1c是来自单一基因的交替转录本，它们在第一个外显子上不同，编码部分酸性激活域。1a蛋白含有一个含有12个带负电氨基酸的长激活域，而1c蛋白含有一个只有6个带负电氨基酸的短激活域。如前所述，SREBP-1a转基因小鼠的肝脏由于甘油三酯和胆固醇的积累而大量增大，SREBP-1c转基因小鼠的肝脏仅轻微增大，甘油三酯仅适度增加，但胆固醇未增加，低密度脂蛋白受体和几种胆固醇生物合成酶的mrna在SREBP-1a转基因小鼠中升高，而在1c转基因小鼠中没有升高。脂肪酸合成酶和乙酰辅酶a羧化酶的mrna在1a动物中升高了9倍和16倍，而在1c动物中仅升高了2倍和4倍。转染细胞的实验证实，当SREBP-1c和SREBP-1a的表达水平接近于未转染细胞时，SREBP-1c的转录激活因子比SREBP-1a弱得多，SREBP-1c只有在超生理水平表达时才成为强激活因子。我们得出结论，SREBP-1a是SREBP-1最活跃的形式，当细胞需要较低的转录率调节胆固醇和脂肪酸代谢的基因时，SREBP-1c可能会产生。
We have produced transgenic mice whose livers express a dominant positive NH2-terminal fragment of sterol regulatory element binding protein-1c (SREBP-1c). Unlike full-length SREBP-1c, the NH2-terminal fragment enters the nucleus without a requirement for proteolytic release from cell membranes, and hence it is immune to downregulation by sterols, We compared SREBP-1c transgenic mice with a line of transgenic mice that produces an equal amount of the NH2-terminal fragment of SREBP-1a. SREBP-1a and -1c are alternate transcripts from a single gene that differ in the first exon, which encodes part of an acidic activation domain. The 1a protein contains a long activation domain with 12 negatively charged amino acids, whereas the 1c protein contains a short activation domain with only 6 such amino acids. As previously reported, livers of the SREBP-1a transgenic mice were massively enlarged, owing to accumulation of triglycerides and cholesterol, SREBP-1c transgenic livers were only slightly enlarged with only a moderate increase in triglycerides, but not cholesterol, The mRNAs for the LDL receptor and several cholesterol biosynthetic enzymes were elevated in SREBP-1a transgenic mice, but not in 1c transgenic mice. The mRNAs for fatty acid synthase and acetyl CoA carboxylase were elevated 9- and 16-fold in 1a animals, but only 2- and 4-fold in 1c animals. Experiments with transfected cells confirmed that SREBP-1c is a much weaker activator of transcription than SREBP-1a when both are expressed at levels approximating those found in nontransfected cells, SREBP-1c became a strong activator only when expressed at supraphysiologic levels, We conclude that SREBP-1a is the most active form of SREBP-1 and that SREBP-1c may be produced when cells require a lower rate of transcription of genes regulating cholesterol and fatty acid metabolism.