Regulation of Cholesterol Biosynthetic Genes by the EGR Family of Transcription Factors

Abstract

Recent work has shown that the Egr2 transcription factor plays a direct role in inducing transcription of cholesterol biosynthetic genes during myelination of peripheral nerves. Myelination requires a considerable amount of de novo cholesterol synthesis in Schwann cells, and mice lacking Egr2 show a decrease in cholesterol biosynthetic gene transcription despite little change in SREBP levels. To determine if Egr family members play a similar role in other tissues, we have investigated the role of Egr1 in regulation of cholesterol biosynthetic genes in liver. Egr1 is induced by insulin both in vitro and in vivo, and therefore could mediate the insulin‐dependent induction of hepatic cholesterol biosynthesis. Using chromatin immunoprecipitation assays, we have shown a >4‐fold insulin‐dependent increase in Egr1 binding to the Hmgcr and Cyp51 promoters in the H4IIE liver cell line. The analysis has been extended to detection of Egr1 binding to promoters in liver, which reveals a >5‐fold induction in Egr1 binding to the Hmgcr and Mod1 promoters in mouse liver in response to feeding as well as an increase in expression of these genes. Overall, we have identified Egr1 as a potential regulator of hepatic cholesterol biosynthesis. This work was supported by a grant from the American Heart Association, 0650102Z.