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 () and Sung Hee Baek ()
Additional contact information
Kyeongkyu Kim: Creative Research Initiatives Center for Chromatin Dynamics, Seoul National University
Kyungjin Boo: Creative Research Initiatives Center for Chromatin Dynamics, Seoul National University
Young Suk Yu: Creative Research Initiatives Center for Chromatin Dynamics, Seoul National University
Se Kyu Oh: Creative Research Initiatives Center for Chromatin Dynamics, Seoul National University
Hyunkyung Kim: Creative Research Initiatives Center for Chromatin Dynamics, Seoul National University
Yoon Jeon: Research Institute, National Cancer Center
Jinhyuk Bhin: Institute for Basic Science, DGIST
Daehee Hwang: Institute for Basic Science, DGIST
Keun Il Kim: Sookmyung Women’s University
Jun-Su Lee: Keimyung University School of Medicine
Seung-Soon Im: Keimyung University School of Medicine
Seul Gi Yoon: College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul National University
Il Yong Kim: College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul National University
Je Kyung Seong: College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul National University
Ho Lee: Research Institute, National Cancer Center
Sungsoon Fang: BK21 Plus Project for Medical Science, Gangnam Severance Hospital, Yonsei University College of Medicine
Sung Hee Baek: Creative Research Initiatives Center for Chromatin Dynamics, Seoul National University

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00215-1

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