IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells: evidence that IDH1 may regulate lipogenesis in hepatic cells
IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells: evidence that IDH1 may regulate lipogenesis in hepatic cells
复制标题
DOI：
10.1194/jlr.m300285-jlr200
复制
发表时间：
2003-11-01
影响因子：
6.5
通讯作者：
Guan, GM
中科院分区：
文献类型：
--
作者：
Shechter, I;Dai, PH;Guan, GM
在缺乏类固醇的HepG2细胞中，胞浆NADP依赖的异柠檬酸脱氢酶(IDH1)的mRNA水平增加2.3倍，NADP异柠檬酸脱氢酶(IDH)的酶活性增加63%。在相同的条件下，依赖于NADP和NAD的线粒体酶的mRNA水平表现出有限的调控或缺乏调控。固醇调节转录所需且充分的核苷酸序列位于IDH1分泌的碱性磷酸酶启动子-报告基因的67bp区域内。IDH1启动子被SREBP-1a在细胞中的表达完全激活，在较小程度上被SREBP-2激活。含有CAAT和GC-Box的23个核苷酸的5‘端截断导致6.5%的剩余活性。参与固醇调节元件结合蛋白(SREBPs)激活的启动子区域位于-44到-25核苷酸之间。突变分析在该区域内发现了IDH1-SRE序列元件GTGGGCTGAG，它与SREBPs结合。与启动子的激活类似，含有IDH1-SRE元件的探针与SREBP-1a相比显示出优先结合SREBP-1a的能力，而不是SREBP-2.jlr这些结果表明IDH1的活性受胆固醇和脂肪酸生物合成途径的协调调节，并提示它是这些途径所需胞浆NADPH的来源。IDH1基因转录受SRFBP-1a和SREBP-2的调节和激活：IDH1可能调节肝细胞的脂肪生成。
The mRNA level for cytosolic NADP-dependent isocitrate dehydrogenase (IDH1) increases 2.3-fold, and enzyme activity of NADP-isocitrate dehydrogenase (IDH) 63%, in sterol-deprived HepG2 cells. The mRNA levels of the NADP- and NAD-dependent mitochondrial enzymes show limited or lack of regulation under the same conditions. Nucleotide sequences that are required, and sufficient, for the sterol regulation of transcription are located within a 67 bp region of an IDH1-secreted alkaline phosphatase promoter-reporter gene. The IDH1 promoter is fully activated by the expression of SREBP-1a in the cells and, to a lesser degree, by that of SREBP-2. A 5'-end truncation of 23 bp containing a CAAT and a GC-Box results in 6.5% residual activity. The promoter region involved in the activation by the sterol regulatory element binding proteins (SREBPs) is located at nucleotides -44 to -25. Mutagenesis analysis identified within this region the IDH1-SRE sequence element GTGGGCTGAG, which binds the SREBPs. Similar to the promoter activation, electrophoretic mobility shifts of probes containing the IDH1-SRE element exhibit preferential binding to SREBP-la, as compared with SREBP-2.jlr These results indicate that IDH1 activity is coordinately regulated with the cholesterol and fatty acid biosynthetic pathways and suggest that it is the source for the cytosolic NADPH required by these pathways.-Shechter, I., P. Dai, L. Huo, and G. Guan. IDH1 gene transcription is sterol regulated and activated by SRFBP-1a and SREBP-2 in human hepatoma HepG2 cells: evidence that IDH1 may regulate lipogenesis in hepatic cells.