Regulation of hepatic Insig-2 by the farnesoid X receptor

Activation of the farnesoid X receptor (FXR alpha) 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 FXR alpha agonists or infected with constitutively active FXR alpha. No such induction was observed in agonist-treated FXR alpha(-/-) mice. Further analysis, which included EMSAs, reporter gene activation, and chromatin immunoprecipitation, identified two functional FXR alpha response elements within intron 2 of the mouse Insig-2 gene. In addition to increasing hepatic Insig-2 protein levels in wild-type mice, FXR alpha activation also reduced lanosterol 14 alpha-demethylase mRNA levels and 3-hydroxy-3-methyl-glutaryl-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 FXR alpha activation to regulation of genes involved in cholesterol synthesis.