Frequent modulation of the sterol regulatory element binding protein (SREBP) by chemical exposure in the livers of rats

Abstract

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 [26] was used to identify microarray comparisons from rat liver that exhibited significant positive or negative correlation to the biomarker using the Running Fisher test. 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.