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ROR alpha controls hepatic lipid homeostasis via negative regulation of PPAR gamma transcriptional network
- ROR alpha controls hepatic lipid homeostasis via negative regulation of PPAR gamma transcriptional network
- 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
- DGIST Authors
- Bhin, Jinhyuk; Hwang, Daehee
- Issue Date
- Nature Communications, 8
- Article Type
- Diet Induced Obesity; Expression; Fatty Liver; Insulin Resistance; Large Gene Lists; Metabolic Syndrome; Mus; Orphan Nuclear Receptors; Rev Erb; RNA Seq; Staggerer Mouse
- 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. © 2017 The Author(s).
- Nature Publishing Group
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