Regulation of hepatic Insig-2 by the farnesoid X receptor.
Activation of the farnesoid X receptor (FXRalpha) 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 FXRalpha agonists or infected with constitutively active FXRalpha. No such induction was observed in agonist-treated FXRalpha-/- mice. Further analysis, which included EMSAs, reporter gene activation, and chromatin immunoprecipitation, identified two functional FXRalpha response elements within intron 2 of the mouse Insig-2 gene. In addition to increasing hepatic Insig-2 protein levels in wild-type mice, FXRalpha activation also reduced lanosterol 14alpha-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 FXRalpha activation to regulation of genes involved in cholesterol synthesis.
Hubbert
Melissa L
ML
Department of Biological Chemistry, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, California 90095, USA.
Zhang
Yanqiao
Y
Lee
Florence Y
FY
Edwards
Peter A
PA
D000818:Animals; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004268:DNA-Binding Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D010088:Oxidoreductases / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D050436:Regulatory Elements, Transcriptional; D058886:Sterol 14-Demethylase; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000099150:Receptor, Farnesoid X-Activated
D002784:Cholesterol; D003577:Cytochrome P-450 Enzyme System; D004268:DNA-Binding Proteins; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent; D008565:Membrane Proteins; D010088:Oxidoreductases; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D058886:Sterol 14-Demethylase; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C506120:Insig2 protein, mouse; C548415:Cyp51 protein, mouse