RORα controls hepatic lipid homeostasis via negative regulation of PPARγ transcriptional network Journal Articles uri icon

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  • AbstractThe retinoic acid receptor-related orphan receptor-α (RORα) is an important regulator of various biological processes, including cerebellum development, circadian rhythm and cancer. Here, we show that hepatic RORα controls lipid homeostasis by negatively regulating transcriptional activity of peroxisome proliferators-activated receptor-γ (PPARγ) that mediates hepatic lipid metabolism. Liver-specific Rorα-deficient mice develop hepatic steatosis, obesity and insulin resistance when challenged with a high-fat diet (HFD). Global transcriptome analysis reveals that liver-specific deletion of Rorα leads to the dysregulation of PPARγ signaling and increases hepatic glucose and lipid metabolism. RORα specifically binds and recruits histone deacetylase 3 (HDAC3) to PPARγ target promoters for the transcriptional repression of PPARγ. PPARγ antagonism restores metabolic homeostasis in HFD-fed liver-specific Rorα deficient mice. Our data indicate that RORα has a pivotal role in the regulation of hepatic lipid homeostasis. Therapeutic strategies designed to modulate RORα activity may be beneficial for the treatment of metabolic disorders.


  • Kim, Kyeongkyu
  • Boo, Kyungjin
  • Yu, Young Suk
  • Oh, Se Kyu
  • Kim, Hyunkyung
  • Jeon, Yoon
  • Bhin, Jinhyuk
  • Hwang, Daehee
  • Kim, Keun Il
  • Lee, Jun-Su
  • Im, Seung-Soon
  • Yoon, Seul Gi
  • Kim, Il Yong
  • Seong, Je Kyung
  • Lee, Ho
  • Fang, Sungsoon
  • Baek, Sung Hee

publication date

  • July 31, 2017