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Cholesterol biosynthesic enzymes and inborn errors

胆固醇生物合成酶和先天性缺陷

基本信息

批准号：
10044251
负责人：
ONO Teruo
金额：
$ 5.12万
依托单位：
Niigata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

The present study was undertaken to determine the chromosomal mapping of the human squalene epoxidase gene (SQLE). PCR evidence localizes human SQLE to chromosome 8 by hybrid panel as templete. Since the locus of the Langer-Giedion (LG) syndrome genes (8q24.1), a congenital abnormality, is close to the locus of human SQLE(8q24.1), SQLE is considered the candidate for the LG syndrome gene(s). The human SQLE consisted about 17 kb long and organized into 11 exons and 10 intorns ranging from 87 to 3.2 kb. We characterized a new SREBP-la and a typical NF-Y binding sites in the promoter of the human SE gene. Both sites are functional in the transcriptional levels of SQLE. Transcription of reporter genes of LXR responsive element (LXRE) and human SE promoter were studied with the effects of lipoprotein deficient serum (LPDS) and oxysterols in LXR α-transfected HeLa cells. Compared with LXR α transgene negative cells, LXRE was significantly induced by LPDS in positive cells and 25-hydroxycholesterol reinforced the induction. In contrast, SE was reciprocally suppressed under the same conditions. Transfection of LXR α mutant failed to support LXRE induction and SE suppression. Those induction and supporession were completely dependent on the LXRs overexpression and oxysterol ligands having specific structure. It is suggested that LXRs may involve in cholesterol homeostasis through the action of target gene product(s) of LXRs by suppressing SE, a key synthesizing enzyme of the endogenous oxysterol ligands for LXRs.

本研究的目的是确定人类角鲨烯环氧酶基因 (SQLE) 的染色体图谱。 PCR 证据通过混合组作为模板将人类 SQLE 定位于 8 号染色体。由于先天性异常的Langer-Giedion (LG) 综合征基因(8q24.1) 的位点与人类SQLE(8q24.1) 的位点接近，因此SQLE 被认为是LG 综合征基因的候选基因。人类 SQLE 长约 17 kb，分为 11 个外显子和 10 个内子，长度范围为 87 至 3.2 kb。我们表征了人类 SE 基因启动子中的新 SREBP-1a 和典型 NF-Y 结合位点。这两个位点在 SQLE 的转录水平上都有功能。在 LXR α 转染的 HeLa 细胞中，研究了 LXR 反应元件 (LXRE) 报告基因和人 SE 启动子的转录以及脂蛋白缺陷血清 (LPDS) 和氧甾醇的影响。与LXRα转基因阴性细胞相比，LPDS在阳性细胞中显着诱导LXRE，并且25-羟基胆固醇增强了这种诱导。相比之下，SE 在相同条件下受到相互抑制。 LXR α 突变体的转染不能支持 LXRE 诱导和 SE 抑制。这些诱导和抑制完全依赖于LXRs的过表达和具有特定结构的氧甾醇配体。这表明LXRs可能通过LXRs靶基因产物的作用，通过抑制SE（LXRs内源性氧甾醇配体的关键合成酶）来参与胆固醇稳态。