Characterizing the Effects of Takeda’s Inhibitor on the SREBP Family of Transcription Factors

Abstract

Sterol regulatory element-binding proteins (SREBPs) are a set of transcription factors that bind to the SRE element. This element is involved in regulating expression of genes involved in cholesterol and fatty acid synthesis as well as the SREBPs themselves. This could make them a valuable drug target for treating non-alcoholic steatohepatitis (NASH), the third largest cause of liver transplants in the US. Takeda developed a series of compounds that were able to selectively inhibit SREBPs as an off target effect through an unknown mechanism. To examine this effect a dual luciferase assay was used to measure the expression of wild-type and mutant SREBP promoters when treated with these compounds. It was found that these compounds equally inhibit all SREBP promoters, regardless of the presence or absence of SRE elements. This suggests that these compounds inhibit SREBP expression through some shared regulatory element that is not the SRE.