Glucocorticoids promote hepatic cholestasis in mice by inhibiting the transcriptional activity of the farnesoid X receptor

Gastroenterology. 2012 Dec;143(6):1630-1640.e8. doi: 10.1053/j.gastro.2012.08.029. Epub 2012 Aug 23.


Background & aims: Glucocorticoids have potent anti-inflammatory effects, but also can cause insulin resistance, osteoporosis, and muscle wasting, preventing their long-term use. Glucocorticoids also have been associated with the development of hepatic cholestasis and gallstone disease, but little is known about their pathogenic mechanisms.

Methods: We analyzed levels of bile acids (BAs) and glucocorticoids in serum samples from patients with Cushing disease and obese individuals (body mass index, >30). C57BL/6 mice were injected with dexamethasone and db/db obese mice were injected with glucocorticoid receptor (GR) antagonists or small hairpin RNAs. We analyzed farnesoid X receptor (FXR) signaling in HepG2 cells and cells from mice using immunoprecipitation, luciferase reporter, and glutathione-s-transferase and chromatin immunoprecipitation assays. We analyzed BA metabolism in FXR-/- mice and mice with reduced levels of the transcription factor C-terminal binding protein (CtBP).

Results: Serum levels of BAs were higher in patients with Cushing disease or obesity than in individuals with normal levels of glucocorticoids. Administration of dexamethasone promoted cholestasis and overproduction of BAs in C57BL/6 mice, but not in FXR-/- mice. GR antagonists, or injection of an adenoviral small hairpin RNA against GR, reduced features of hepatic cholestasis in db/db mice. The GR interacted with FXR to reduce its transcriptional activity by recruiting CtBP co-repressor complexes. Mice with reduced levels of CtBP were resistant to induction of hepatic cholestasis by dexamethasone.

Conclusions: Glucocorticoids promote hepatic cholestasis in mice by recruiting CtBP co-repressor complexes to FXR and thereby blocking the transcriptional activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alcohol Oxidoreductases / metabolism
  • Animals
  • Bile Acids and Salts / blood
  • Cholestasis, Intrahepatic / etiology*
  • Cholestasis, Intrahepatic / metabolism
  • Cholestasis, Intrahepatic / physiopathology*
  • DNA-Binding Proteins / metabolism
  • Dexamethasone / pharmacology
  • Disease Models, Animal
  • Female
  • Glucocorticoids / adverse effects*
  • Glucocorticoids / blood
  • Glucocorticoids / pharmacology
  • Hep G2 Cells
  • Homeostasis / drug effects
  • Homeostasis / physiology
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Obese
  • Middle Aged
  • Obesity / blood
  • Obesity / physiopathology
  • Pituitary ACTH Hypersecretion / blood
  • Pituitary ACTH Hypersecretion / physiopathology
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Receptors, Cytoplasmic and Nuclear / physiology
  • Signal Transduction / physiology
  • Transcription, Genetic / drug effects*
  • Transcription, Genetic / physiology
  • Young Adult


  • Bile Acids and Salts
  • DNA-Binding Proteins
  • Glucocorticoids
  • Receptors, Cytoplasmic and Nuclear
  • farnesoid X-activated receptor
  • Dexamethasone
  • Alcohol Oxidoreductases
  • C-terminal binding protein