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

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Title
ROR alpha controls hepatic lipid homeostasis via negative regulation of PPAR gamma transcriptional network
Author(s)
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
Publication Date
2017-07
Journal
NATURE COMMUNICATIONS, v.8, no., pp.162 -
Publisher
NATURE PUBLISHING GROUP
Abstract
The retinoic acid receptor-related orphan receptor-alpha (ROR alpha) is an important regulator of various biological processes, including cerebellum development, circadian rhythm and cancer. Here, we show that hepatic ROR alpha controls lipid homeostasis by negatively regulating transcriptional activity of peroxisome proliferators-activated receptor-gamma (PPAR gamma) that mediates hepatic lipid metabolism. Liver-specific Ror alpha-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 Ror alpha leads to the dysregulation of PPAR gamma signaling and increases hepatic glucose and lipid metabolism. ROR alpha specifically binds and recruits histone deacetylase 3 (HDAC3) to PPAR gamma target promoters for the transcriptional repression of PPAR gamma. PPAR gamma antagonism restores metabolic homeostasis in HFD-fed liver-specific Ror alpha deficient mice. Our data indicate that ROR alpha has a pivotal role in the regulation of hepatic lipid homeostasis. Therapeutic strategies designed to modulate ROR alpha activity may be beneficial for the treatment of metabolic disorders. © The Author(s) 2017
URI
http://pr.ibs.re.kr/handle/8788114/3811
DOI
10.1038/s41467-017-00215-1
ISSN
2041-1723
Appears in Collections:
Center for Plant Aging Research (식물 노화·수명 연구단) > Journal Papers (저널논문)
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