ROR? controls hepatic lipid homeostasis via negative regulation of PPAR? transcriptional network.

ABSTRACT: The retinoic acid receptor-related orphan receptor-? (ROR?) is an important regulator of various biological processes, including cerebellum development, circadian rhythm and cancer. Here, we show that hepatic ROR? controls lipid homeostasis by negatively regulating transcriptional activity of peroxisome proliferators-activated receptor-? (PPAR?) that mediates hepatic lipid metabolism. Liver-specific Ror?-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 Ror? leads to the dysregulation of PPAR? signaling and increases hepatic glucose and lipid metabolism. ROR? specifically binds and recruits histone deacetylase 3 (HDAC3) to PPAR? target promoters for the transcriptional repression of PPAR?. PPAR? antagonism restores metabolic homeostasis in HFD-fed liver-specific Ror? deficient mice. Our data indicate that ROR? has a pivotal role in the regulation of hepatic lipid homeostasis. Therapeutic strategies designed to modulate ROR? 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 ROR? inhibits PPAR?-mediated transcriptional activity by interacting with HDAC3 and competing for the promoters of lipogenic genes.

SUBMITTER: Kim K 

PROVIDER: S-EPMC5534431 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature