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황성순(의생명과학부) Nat Commun
등록일 : 2017-08-07 오후 4:08:00       조회 : 188
첨   부 :
공동교신저자 황성순(의생명과학부, 강남, BK21), 백성희(서울대)

Nat Commun. 2017 Jul 31ɖ;(1):162. doi: 10.1038/s41467-017-00215-1.
RORα controls hepatic lipid homeostasis via negative regulation of PPARγ transcriptional network.
Kim K1, Boo K1, Yu YS1, Oh SK1, Kim H1, Jeon Y2, Bhin J3, Hwang D3, Kim KI4, Lee JS5, Im SS5, Yoon SG6,7, Kim IY6,7, Seong JK6,7,8, Lee H2, Fang S9, Baek SH10.

Author information
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.6Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, South Korea.7Korea Mouse Phenotyping Center, Seoul, 08826, South Korea.8BK21 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.9Severance Biomedical Science Institute, BK21 Plus Project for Medical Science, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, 06273, South Korea. sfang@yuhs.ac.10Department of Biological Sciences, Creative Research Initiatives Center for Chromatin Dynamics, Seoul National University, Seoul, 08826, South Korea. sbaek@snu.ac.kr.

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.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.
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