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Regulation of Hepatic Insig-2 by the Farnesoid X Receptor

Departments of Biological Chemistry (M.L.H., F.Y.L., P.A.E.) and Medicine (M.L.H., Y.Z., F.Y.L., P.A.E.), David Geffen School of Medicine, and the Molecular Biology Institute at UCLA (P.A.E.), Los Angeles, California 90095

Address all correspondence and requests for reprints to: Peter A. Edwards, Department of Biological Chemistry, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 33-257 CHS, Los Angeles, California 90095. E-mail: pedwards{at}mednet.ucla.edu.

Activation of the farnesoid X receptor (FXR) 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 agonists or infected with constitutively active FXR. No such induction was observed in agonist-treated FXR^–/– mice. Further analysis, which included EMSAs, reporter gene activation, and chromatin immunoprecipitation, identified two functional FXR 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 activation also reduced lanosterol 14-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 FXR activation to regulation of genes involved in cholesterol synthesis.

NURSA Molecule Pages Link:

Nuclear Receptors:   SHP  |  FXRα

Ligands:   GW4064

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