DIETARY-CHOLESTEROL INCREASES TRANSCRIPTION OF THE HUMAN CHOLESTERYL ESTER TRANSFER PROTEIN GENE IN TRANSGENIC MICE - DEPENDENCE ON NATURAL FLANKING SEQUENCES
DIETARY-CHOLESTEROL INCREASES TRANSCRIPTION OF THE HUMAN CHOLESTERYL ESTER TRANSFER PROTEIN GENE IN TRANSGENIC MICE - DEPENDENCE ON NATURAL FLANKING SEQUENCES
复制标题
DOI：
10.1172/jci115993
复制
发表时间：
1992-10-01
影响因子：
15.9
通讯作者：
TALL, A
中科院分区：
文献类型：
--
作者：
JIANG, XC;AGELLON, LB;TALL, A
为了研究人胆固醇酯转移蛋白（CETP）基因表达的调控，使用连接到人CETP基因的天然侧翼序列的CETP小基因制备转基因小鼠。通过使用含有3.2kb上游和2.0kb下游侧翼序列的转基因，产生了五个不同系的转基因小鼠。在标准实验室饮食或高脂肪、高胆固醇饮食中测定各种组织中CETP mRNA的丰度。在三种转基因小鼠中，表达人CETP mRNA的组织与人类相似（肝、脾、小肠、肾和脂肪组织）;在两种转基因小鼠中，表达受到更多限制。有一个显着的（4-10倍）诱导肝CETP mRNA的高脂肪，高胆固醇饮食。肝CETP mRNA的增加伴随着CETP转基因转录速率的5倍增加，以及血浆CETP质量和活性的2.5倍增加。相比之下，CETP转基因小鼠，其中的CETP小基因连接到金属硫蛋白启动子，而不是自己的侧翼序列，显示在肝脏CETP mRNA在响应高胆固醇饮食没有变化。因此，（a）CETP小基因或天然侧翼序列含有指导真实组织特异性表达的元件;（B）高胆固醇饮食诱导CETP转基因转录，导致肝CETP mRNA和血浆CETP增加;（c）这种胆固醇应答需要人CETP基因的天然侧翼区中含有的DNA序列。
To investigate the regulation of expression of the human cholesteryl ester transfer protein (CETP) gene, transgenic mice were prepared using a CETP minigene linked to the natural flanking sequences of the human CETP gene. By using a transgene containing 3.2 kb of upstream and 2.0 kb of downstream flanking sequence, five different lines of transgenic mice were generated. The abundance of CETP mRNA in various tissues was determined on standard laboratory diet or high fat, high cholesterol diets. In three lines of transgenic mice the tissues expressing the human CETP mRNA were similar to those in humans (liver, spleen, small intestine, kidney, and adipose tissue); in two lines expression was more restricted. There was a marked (4-10-fold) induction of liver CETP mRNA in response to a high fat, high cholesterol diet. The increase in hepatic CETP mRNA was accompanied by a fivefold increase in transcription rate of the CETP transgene, and a 2.5-fold increase in plasma CETP mass and activity. In contrast, CETP transgenic mice, in which the CETP minigene was linked to a metallothionein promoter rather than to its own flanking sequences, showed no change in liver CETP mRNA in response to a high cholesterol diet. Thus (a) the CETP minigene or natural flanking sequences contain elements directing authentic tissue-specific expression; (b) a high cholesterol diet induces CETP transgene transcription, causing increased hepatic CETP mRNA and plasma CETP; (c) this cholesterol response requires DNA sequences contained in the natural flanking regions of the human CETP gene.