| First Author | Kim K | Year | 2017 |
| Journal | Nat Commun | Volume | 8 |
| Issue | 1 | Pages | 162 |
| PubMed ID | 28757615 | Mgi Jnum | J:248803 |
| Mgi Id | MGI:5921066 | Doi | 10.1038/s41467-017-00215-1 |
| Citation | Kim K, et al. (2017) RORalpha controls hepatic lipid homeostasis via negative regulation of PPARgamma transcriptional network. Nat Commun 8(1):162 |
| abstractText | The retinoic acid receptor-related orphan receptor-alpha (RORalpha) is an important regulator of various biological processes, including cerebellum development, circadian rhythm and cancer. Here, we show that hepatic RORalpha controls lipid homeostasis by negatively regulating transcriptional activity of peroxisome proliferators-activated receptor-gamma (PPARgamma) that mediates hepatic lipid metabolism. Liver-specific Roralpha-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 Roralpha leads to the dysregulation of PPARgamma signaling and increases hepatic glucose and lipid metabolism. RORalpha specifically binds and recruits histone deacetylase 3 (HDAC3) to PPARgamma target promoters for the transcriptional repression of PPARgamma. PPARgamma antagonism restores metabolic homeostasis in HFD-fed liver-specific Roralpha deficient mice. Our data indicate that RORalpha has a pivotal role in the regulation of hepatic lipid homeostasis. Therapeutic strategies designed to modulate RORalpha 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 RORalpha inhibits PPARgamma-mediated transcriptional activity by interacting with HDAC3 and competing for the promoters of lipogenic genes. |
