Mifepristone (RU486) inhibits dietary lipid digestion by antagonizing the role of glucocorticoid receptor on lipase transcription

Peng Ma; Yao Zhang; Qiying Liang; Youjie Yin; Saifei Wang; Ruolei Han; Chunyu Huo; Hansong Deng

doi:10.1016/j.isci.2021.102507

Mifepristone (RU486) inhibits dietary lipid digestion by antagonizing the role of glucocorticoid receptor on lipase transcription

iScience. 2021 May 12;24(6):102507. doi: 10.1016/j.isci.2021.102507. eCollection 2021 Jun 25.

Authors

Peng Ma¹, Yao Zhang¹, Qiying Liang¹, Youjie Yin¹, Saifei Wang¹, Ruolei Han¹, Chunyu Huo¹, Hansong Deng¹

Affiliation

¹ Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, 6B, Shixun Bldg, 1239 Siping Road, Yangpu District, Shanghai, 20092, China.

Abstract

Lipid digestion and absorption are tightly regulated to cope with metabolic demands among tissues. How these processes are coordinated is not well characterized. Here, we found that mifepristone (RU486) prevents lipid digestion both in flies and mice. In flies, RU486 administration suppresses lipid digestion by transcriptional downregulating Magro in guts. Similarly, intestinal lipid uptake in mice was also suppressed by RU486 through the glucocorticoid receptor (GR). Further studies showed that the pancreatic lipase Pnlip is a direct transcriptional target of GR in pancreas tissues. Glucocorticoid levels in mice fed a high fat diet (HFD) are significantly lower than those fed on a conventional diet, and RU486 administration inhibits HFD-induced obesity both in mice and flies. Our findings identified a novel mechanism of RU486 functions as a GR antagonist systematically regulating lipid metabolism, providing new insight on the role of Glucocorticoid/GR in Cushing disease, diabetes, and other related metabolic syndromes.

Keywords: Cellular physiology; Lipid; Metabolic engineering.