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

Yan Lu, Zhijian Zhang, Xuelian Xiong, Xiaolin Wang, Jin Li, Guojun Shi, Jian Yang, Xianfeng Zhang, Huijie Zhang, Jie Hong, Xuefeng Xia, Guang Ning, Xiaoying Li

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

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.

Original languageEnglish (US)
JournalGastroenterology
Volume143
Issue number6
DOIs
StatePublished - Jan 1 2012

Keywords

  • Bile Acid Metabolism
  • Liver Disease
  • Nuclear Receptor
  • Small Heterodimer Partners

ASJC Scopus subject areas

  • Gastroenterology

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