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A gene expression biomarker identifies factors that modulate sterol regulatory element binding protein

J. Rooney,B. Chorley,J. Corton

Published 2019 in Computational Toxicology

ABSTRACT

Abstract Lipid levels are regulated in mammals by sterol regulatory element-binding proteins (SREBPs). To identify chemicals that might cause steatosis through SREBP, a mouse gene expression biomarker was characterized that can predict modulation of SREBP family members. Using microarray comparisons, genes were identified that were commonly regulated by constitutively-active SREBP family members and required SREBP cleavage-activating protein. Pair-wise correlations between the biomarker and microarray profiles were measured using the Running Fisher algorithm; the test achieved a balanced accuracy of 95% and 94% for prediction of SREBP activation or suppression, respectively. Our approach uncovered a number of previously unrecognized features of SREBP regulation in a mouse liver gene expression compendium of ∼2600 microarray comparisons. SREBP modulation is 1) a relatively common phenomenon, with 10% and 12% of all comparisons exhibiting activation or suppression, respectively; 2) often modulated by diets and chemicals; 3) linked to steatosis induced by perfluoroalkyl acids; and 4) in most cases (77%) leads to coordinated increases or decreases in lipogenic and cholesterogenic genes. Conditions were identified in which regulation was uncoupled. Together, these findings identify chemicals that perturb SREBP activation and demonstrate a diversity of coupling levels among lipogenic and cholesterogenic genes across experimental conditions.

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