RORα controls hepatic lipid homeostasis via negative regulation of PPARγ transcriptional network

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

Research output: Contribution to journalArticlepeer-review

96 Citations (Scopus)


The 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.

Original languageEnglish
Article number162
JournalNature communications
Issue number1
Publication statusPublished - 2017 Dec 1
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2017 The Author(s).

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General Physics and Astronomy


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