간에서의 RORa에 의한 지방 항상성 유지 조절 기작에 관한 연구

Abstract

Hepatic metabolic dysregulation has been shown to induce fatty liver, insulin resistance and obesity. The retinoic acid receptor-related orphan receptor a (RORa) is an important regulator of various biological processes, including cerebellum development, circadian rhythm, and cancer. Here, I find that hepatic RORa regulates lipid homeostasis by negatively regulating transcriptional activity of peroxisome proliferators-activated receptor g (PPARg), a nuclear receptor that mediates hepatic lipid metabolism. Liver-specific Rora 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 Rora leads to the dysregulation of PPARg signaling to increase hepatic glucose and lipid metabolism. RORa specifically binds and recruits HDAC3 to the PPARg target promoters for the transcriptional repression of PPARg activity. Finally, PPARg antagonism remarkably restores metabolic homeostasis in HFD-fed liver-specific Rora deficient mice. Taken together, my data indicate that RORa plays a pivotal role in the regulation of hepatic lipid homeostasis. Therefore, therapeutic strategies designed to modulate RORa activity may be beneficial for the treatment of metabolic disorders, including hepatic steatosis and obesity.