Regulation of cholesterol 7α-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRα)
Regulation of cholesterol 7α-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRα)
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DOI：
10.1016/s0378-1119(00)00518-7
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发表时间：
2001-01-10
期刊：
影响因子：
3.5
通讯作者：
Stroup, D
中科院分区：
文献类型：
--
作者：
Chiang, JYL;Kimmel, R;Stroup, D
胆固醇7α-羟化酶基因（CYP7A1）在调节胆汁酸生物合成和胆固醇稳态中发挥重要作用。氧甾醇受体 LXR 刺激 CYP7A1 转录，而胆汁酸受体 FXR 抑制 CYP7A1 转录。本研究的目的是研究 LXR α 在其天然启动子和细胞环境中对大鼠、人类和仓鼠 CYP7A1 转录的调节作用。用 LXR α 和 RXR α 表达质粒共转染强烈刺激 HepG2 细胞中的大鼠 CYP7A1/荧光素酶报告基因活性，并且不需要氧甾醇。然而，LXR α 对仓鼠的影响要小得多，并且对 HepG2 细胞中人 CYP7A1 启动子活性没有显着影响。在中国仓鼠卵巢细胞中，与 LXR α 共转染对报告基因活性的刺激不到 2 倍，而添加 22(R)-羟基胆固醇对大鼠、人类和仓鼠 CYP7A1 启动子活性产生小但显着的刺激。在先前鉴定的大鼠CYP7A1的胆汁酸反应元件中，至少两个具有4碱基间隔（DR4）和5碱基间隔（DR5）的AGGTCA样序列的直接重复能够结合LXRα/RXRα并赋予LXRα刺激。然而，LXR α 不与人类基因的相应序列结合，并且与仓鼠和小鼠 DR4 序列弱结合。因此，大鼠和小鼠具有通过LXR α介导的CYP7A1转录刺激将胆固醇转化为胆汁酸的不寻常的能力，而其他物种对胆固醇没有反应并在高胆固醇饮食中出现高胆固醇血症。 (C) 2001 Elsevier Science B.V. 保留所有权利。
The cholesterol 7 alpha -hydroxylase gene (CYP7A1) plays an important role in regulation of bile acid biosynthesis and cholesterol homeostasis. Oxysterol receptor, LXR, stimulates, whereas the bile acid receptor, FXR, inhibits CYP7A1 transcription. The goal of this study was to investigate the role of LXR alpha on the regulation of rat, human and hamster CYP7A1 transcription in its native promoter and cellular context. Cotransfection with LXR alpha and RXR alpha expression plasmids strongly stimulated rat CYP7A1/luciferase reporter activity in HepG2 cells and oxysterol was not required. However, LXR alpha had much less effect on hamster and no significant effect on human CYP7A1 promoter activity in HepG2 cells. In Chinese hamster ovary cells, cotransfection with LXR alpha stimulated reporter activity by less than 2-fold and addition of 22(R)-hydroxycholesterol caused a small but significant stimulation of rat, human and hamster CYP7A1 promoter activity. At least two direct repeats of AGGTCA-like sequences with 4-base spacing (DR4) and five-base spacing (DR5), in previously identified bile acid response elements of the rat CYP7A1 were able to bind LXR alpha /RXR alpha and confer LXR alpha stimulation. However, LXR alpha did not bind to the corresponding sequences of the human gene and bound weakly to hamster and mouse DR4 sequences. Therefore, rats and mice have the unusual capacity to convert cholesterol to bile acids by LXR alpha -mediated stimulation of CYP7A1 transcription, whereas other species do not respond to cholesterol and develop hypercholesterolemia on a diet high in cholesterol. (C) 2001 Elsevier Science B.V. All rights reserved.