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
Affiliations
Peng Ma
Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, 6B, Shixun Bldg, 1239 Siping Road, Yangpu District, Shanghai, 20092, China
Yao Zhang
Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, 6B, Shixun Bldg, 1239 Siping Road, Yangpu District, Shanghai, 20092, China
Qiying Liang
Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, 6B, Shixun Bldg, 1239 Siping Road, Yangpu District, Shanghai, 20092, China
Youjie Yin
Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, 6B, Shixun Bldg, 1239 Siping Road, Yangpu District, Shanghai, 20092, China
Saifei Wang
Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, 6B, Shixun Bldg, 1239 Siping Road, Yangpu District, Shanghai, 20092, China
Ruolei Han
Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, 6B, Shixun Bldg, 1239 Siping Road, Yangpu District, Shanghai, 20092, China
Chunyu Huo
Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, 6B, Shixun Bldg, 1239 Siping Road, Yangpu District, Shanghai, 20092, China
Hansong Deng
Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, 6B, Shixun Bldg, 1239 Siping Road, Yangpu District, Shanghai, 20092, China; Corresponding author
Summary: 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.
