ROR\u03b1 controls hepatic lipid homeostasis via negative regulation of PPAR\u03b3 transcriptional network

Se Kyu Oh,Je Kyung Seong,Ho Lee,Kyungjin Boo,Seung-Soon Im,Il Yong Kim,Sung Hee Baek,Daehee Hwang,Jinhyuk Bhin,Seul Gi Yoon,Sungsoon Fang,Keun Il Kim,Hyunkyung Kim,Young Suk Yu,Kyeongkyu Kim,Yoon Jeon,Jun-Su Lee

doi:10.1038/s41467-017-00215-1

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.

Highlights

The retinoic acid receptor-related orphan receptor-α (RORα) is an important regulator of various biological processes, including cerebellum development, circadian rhythm and cancer
No obvious defects were observed in mice on control diet (CD) (Supplementary Fig. 1c), high-fat diet (HFD)-fed RORαLKO mice were found to produce far less CO2, consume less O2 and expend less energy than RORαf/f littermates, indicating that oxidative phosphorylation is impaired by the hepatic deletion of RORα (Fig. 1n and Supplementary Fig. 1d)
We demonstrate that enhanced peroxisome proliferators-activated receptor-γ (PPARγ) transcriptional activity by RORα deficiency is de-activated by PPARγ antagonism to restore metabolic homeostasis, including body weight gain, hepatic steatosis and glucose and lipid metabolism

Summary

Introduction

The retinoic acid receptor-related orphan receptor-α (RORα) is an important regulator of various biological processes, including cerebellum development, circadian rhythm and cancer. 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. We report that RORα plays a key role to control hepatic lipid metabolism to protect against diet-induced obesity and hepatic steatosis, using liver-specific Rorα-deficient mouse model. High-fat diet (HFD)-fed liver-specific Rorα deficient mice (RORαLKO mice) show severe metabolic defects, including hepatic steatosis, obesity, and insulin resistance, no physiological changes have been observed with control diet (CD). PPARγ antagonism by using PPARγ antagonist GW9662, largely ameliorates body weight gain and hepatic steatosis in HFD-fed RORαLKO mice, indicating that dysregulated PPARγ signaling is a critical metabolic cue, leading to metabolic defects in HFD-fed RORαLKO mice.

Methods

Results

Conclusion