title: Glucocorticoids promote hepatic cholestasis in mice by inhibiting the transcriptional activity of the farnesoid X receptor.
abstract: OBJECTIVE
  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.
authors.affiliation: Shanghai Institute of Endocrinology and Metabolism, Department of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xuelian
authors.initials: X
authors.lastname: Xiong
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Wang
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.forename: Guojun
authors.initials: G
authors.lastname: Shi
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Zhang
authors.forename: Huijie
authors.initials: H
authors.lastname: Zhang
authors.forename: Jie
authors.initials: J
authors.lastname: Hong
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Xia
authors.forename: Guang
authors.initials: G
authors.lastname: Ning
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Li
mesh_terms: D000293:Adolescent; D000328:Adult; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood; D002780:Cholestasis, Intrahepatic / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005938:Glucocorticoids / Q000009:adverse effects* / Q000097:blood / Q000494:pharmacology; D056945:Hep G2 Cells; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D008875:Middle Aged; D009765:Obesity / Q000097:blood / Q000503:physiopathology; D047748:Pituitary ACTH Hypersecretion / Q000097:blood / Q000503:physiopathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology; D055815:Young Adult; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000429:Alcohol Oxidoreductases; D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D003907:Dexamethasone; D005938:Glucocorticoids; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C096794:C-terminal binding protein