RORα controls hepatic lipid homeostasis via negative regulation of PPARγ transcriptional network

• Published in: Nature communications 2017-07, Vol.8 (1), p.162-15, Article 162
• Main Authors: Kim, Kyeongkyu, Boo, Kyungjin, Yu, Young Suk, Oh, Se Kyu, Kim, Hyunkyung, Jeon, Yoon, Bhin, Jinhyuk, Hwang, Daehee, Kim, Keun Il, Lee, Jun-Su, Im, Seung-Soon, Yoon, Seul Gi, Kim, Il Yong, Seong, Je Kyung, Lee, Ho, Fang, Sungsoon, Baek, Sung Hee
• Format: Article
• Language: English
• Subjects: 631/80/86/388; 692/4020/1503/1607/2750; 692/699/2743/2037; Animals; Bile; Circadian rhythm; Diet, High-Fat; Fatty liver; Fatty Liver - genetics; Gene Expression Regulation - genetics; Gene regulation; Gene Regulatory Networks; Glucose - metabolism; Histone Deacetylases - metabolism; Homeostasis; Humanities and Social Sciences; Insulin resistance; Insulin Resistance - genetics; Lipid metabolism; Lipid Metabolism - genetics; Lipogenesis - genetics; Liver; Liver - metabolism; Metabolic disorders; Metabolism; Mice; multidisciplinary; Nuclear Receptor Subfamily 1, Group F, Member 1 - genetics; Obesity - genetics; Peroxisome proliferator-activated receptors; PPAR gamma - antagonists & inhibitors; PPAR gamma - genetics; Promoter Regions, Genetic - genetics; Promoters; Science; Science (multidisciplinary); Steatosis; Transcription factors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-00215-1

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. ROR α 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.