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Nat. Commun., 8, Article number: 162 (2017) | doi:10.1038/s41467-017-00215-1 RORα controls hepatic lipid homeostasis via negative regulation of PPARγ transcriptional network

Kyeongkyu Kim¹, Kyungjin Boo¹, Young Suk Yu¹, Se Kyu Oh¹, Hyunkyung Kim¹, Yoon Jeon², Jinhyuk Bhin³, Daehee Hwang³, Keun Il Kim⁴, Jun-Su Lee⁵, Seung-Soon Im⁵, Seul Gi Yoon^6,7, Il Yong Kim^6,7, Je Kyung Seong^6,7,8, Ho Lee², Sungsoon Fang^9,* & Sung Hee Baek^1,*¹Department of Biological Sciences, Creative Research Initiatives Center for Chromatin Dynamics, Seoul National University, Seoul 08826, South Korea. ²Graduate School of Cancer Science and Policy, Research Institute, National Cancer Center, Gyeonggi-do 10408, South Korea. ³Department of New Biology and Center for Plant Aging Research, Institute for Basic Science, DGIST, Daegu 42988, South Korea. ⁴Department of Biological Sciences, Sookmyung Women’s University, Seoul 04310, South Korea. ⁵Department of Physiology, Keimyung University School of Medicine, Daegu 42601, South Korea.⁶ Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul National University, Seoul 08826, South Korea. ⁷ Korea Mouse Phenotyping Center, Seoul 08826, South Korea. ⁸ BK21 Plus Program for Creative Veterinary Science Research, BIO-MAX institute, Interdisciplinary Program for Bioinformatics and Program for Cancer Biology, Seoul National University, Seoul 08826, South Korea. ⁹ Severance Biomedical Science Institute, BK21 Plus Project for Medical Science, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, South Korea.

Kyeongkyu Kim and Kyungjin Boo contributed equally to this work.

^*Correspondence to Sungsoon Fang or Sung Hee Baek

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.

논문정보

형식Research article
게재일2017년 07월 (BRIC 등록일 2017-08-02)
연구진국내 연구진
분야 생명과학 > 세포생물학

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