Frequent Modulation of the Sterol Regulatory Element Binding Protein (SREBP) by Chemical Exposure in the Livers of Rats.
Frequent Modulation of the Sterol Regulatory Element Binding Protein (SREBP) by Chemical Exposure in the Livers of Rats.
复制标题
DOI：
10.1016/j.comtox.2019.01.007
复制
发表时间：
2019-01-01
期刊：
影响因子：
--
通讯作者：
Corton, J Christopher
中科院分区：
文献类型：
--
作者：
Corton, J Christopher
甾醇调节元件结合蛋白 (SREBP) 的不当激活可导致非酒精性脂肪肝 (NAFLD)。为了将化学暴露与 SREBP 活性联系起来，使用先前表征的基因表达生物标志物（Rooney 等人，2019）来识别与生物标志物表现出显着正相关或负相关的大鼠肝脏的微阵列比较。通过 9305 种化学剂量-时间微阵列比较检查了 620 种化学物质对 SREBP 活性的影响。研究发现，SREBP 经常受到化学物质暴露的调节，其中 54% 的化学物质影响 SREBP 活性。激活剂包括胆固醇生成抑制剂，可抑制 HMG-CoA 还原酶（他汀类药物）或抑制 Cyp51（康唑类药物）。大多数化学效应都是短暂的，通常持续不超过 2-4 天。在大多数情况下，SREBP 的调节会导致脂肪生成和胆固醇生成基因的协调增加或减少。然而，已确定 570 种化学品暴露条件，其中监管是脱节的。大多数这些情况影响胆固醇生成基因，但对脂肪生成基因没有平行影响。总之，这些发现表明，SREBP 是化学暴露的常见目标，并且脂肪生成和胆固醇生成基因的表达可以分离。
Inappropriate activation of sterol regulatory element-binding proteins (SREBPs) can lead to non-alcoholic fatty liver disease (NAFLD). To link chemical exposure to SREBP activity, a previously characterized gene expression biomarker (Rooney et al., 2019) was used to identify microarray comparisons from rat liver that exhibited significant positive or negative correlation to the biomarker. The effects of 620 chemicals on SREBP activity were examined across 9305 chemical-dose-time microarray comparisons. SREBP was found to be frequently modulated by chemical exposure with 54% of the chemicals affecting SREBP activity. Activators included inhibitors of cholesterogenesis that act to inhibit HMG-CoA reductase (statins) or inhibit Cyp51 (conazoles). Most chemical effects were transient, lasting usually no more than 2-4 days. Modulation of SREBP in most cases led to coordinated increases or decreases in lipogenic and cholesterogenic genes. However, 570 chemical exposure conditions were identified in which regulation was uncoupled. Most of these conditions affected cholesterogenic genes in the absence of parallel effects on lipogenic genes. Together, these findings show that SREBP is a frequent target of chemical exposure and expression of lipogenic and cholesterogenic genes can be uncoupled.