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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 
 NATURE COMMUNICATIONS, Vol.8(162) : 1-15, 2017 
Journal Title
Issue Date
Animals ; Diet, High-Fat ; Fatty Liver/genetics ; Gene Expression Regulation/genetics ; Gene Regulatory Networks ; Glucose/metabolism ; Histone Deacetylases/metabolism ; Homeostasis ; Insulin Resistance/genetics ; Lipid Metabolism/genetics ; Lipogenesis/genetics ; Liver/metabolism ; Mice ; Nuclear Receptor Subfamily 1, Group F, Member 1/genetics ; Obesity/genetics ; PPAR gamma/antagonists & inhibitors ; PPAR gamma/genetics ; Promoter Regions, Genetic/genetics
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.Hepatic steatosis development may result from dysregulation of lipid metabolism, which is finely tuned by several transcription factors including the PPAR family. Here Kim et al. show that the nuclear receptor RORα inhibits PPARγ-mediated transcriptional activity by interacting with HDAC3 and competing for the promoters of lipogenic genes.
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Fang, Sungsoon(황성순) ORCID logo https://orcid.org/0000-0003-0201-5567
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