Regulation of Hepatic Insig-2 by the Farnesoid X Receptor

Activation of the farnesoid X receptor (FXRα) affects genes controlling many pathways, including those involved in bile acid and glucose homeostasis. Here we report that a critical gene involved in cholesterol homeostasis, Insig-2, was induced when mice or cultured cells were treated with FXRα agonists or infected with constitutively active FXRα. No such induction was observed in agonist-treated FXRα−/− mice. Further analysis, which included EMSAs, reporter gene activation, and chromatin immunoprecipitation, identified two functional FXRα response elements within intron 2 of the mouse Insig-2 gene. In addition to increasing hepatic Insig-2 protein levels in wild-type mice, FXRα activation also reduced lanosterol 14α-demethylase mRNA levels and 3-hydroxy-3-methylglutaryl-coenzyme A reductase protein levels. Together, these changes likely account for the decrease in cholesterol synthesis observed after activation of FXR in primary hepatocytes. In conclusion, the current study links hepatic FXRα activation to regulation of genes involved in cholesterol synthesis.