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

Abstract

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