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ROR alpha controls hepatic lipid homeostasis via negative regulation of PPAR gamma transcriptional network

Title
ROR alpha controls hepatic lipid homeostasis via negative regulation of PPAR gamma transcriptional network
Authors
Kim, KyeongkyuBoo, KyungjinYu, Young SukOh, Se KyuKim, HyunkyungJeon, YoonBhin, JinhyukHwang, DaeheeKim, Keun IlLee, Jun-SuIm, Seung-SoonYoon, Seul GiKim, Il YongSeong, Je KyungLee, HoFang, SungsoonBaek, Sung Hee
DGIST Authors
Bhin, Jinhyuk; Hwang, Daehee
Issue Date
2017-07
Citation
Nature Communications, 8
Type
Article
Article Type
Article
Keywords
Diet Induced ObesityExpressionFatty LiverInsulin ResistanceLarge Gene ListsMetabolic SyndromeMusOrphan Nuclear ReceptorsRev ErbRNA SeqStaggerer Mouse
ISSN
2041-1723
Abstract
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).
URI
http://hdl.handle.net/20.500.11750/4447
DOI
10.1038/s41467-017-00215-1
Publisher
Nature Publishing Group
Files:
There are no files associated with this item.
Collection:
ETC1. Journal Articles


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