Farnesoid X receptor (FXR) is a member of metabolism related nuclear receptor family. FXR agonists have been reported to improve blood glucose levels by increasing insulin sensitivity. However, there are some side effects such as lowering the level of high density lipoprotein (HDL) and aggravating obesity after long-term administration of FXR. The antagonistic FXR can reduce body weight and blood glucose, especially can better control postprandial blood glucose. Therefore, the research of FXR antagonists is also one of the hot spots of anti-metabolic diseases. At present, the effect and mechanism of FXR on glucose metabolism are not clear. Therefore, it is important to screen a small molecule FXR antagonist as a probe to explore the mechanism of FXR regulating glucose metabolism.
Type 2 diabetes mellitus (T2DM), a progressive metabolic disease characterized by abnormal glucose and lipid metabolism, has become a serious threat to human health [1,2].
Farnesoid X receptor (FXR) belongs to a member of the nuclear receptor Superfamily  and has been reported to be associated with glucose metabolism. For example, in FXR−/− mice, the level of hepatic gluconeogenic gene expression was decreased after fasting, while blood glucose level and the hepatic glucose production in response to pyruvate challenge were declined . However, the effect and mechanism of FXR regulating glucose metabolism in vivo are not clear. Thus, we aim to screen a small molecule FXR antagonist as a probe to explore the mechanism of FXR regulating glucose metabolism.
Here, we used the AlphaScreen assay to screen the FXR antagonist.Among the compounds, H7 was finally selected for its highly antipathogenic activity against FXR. Finally, H7 antagonized GW4064-induced reporter gene stimulation in transactivation assay, indicating that H7 was an FXR antagonist.
 Chatterjee S, Khunti K, Davies MJ. Type 2 diabetes. Lancet 2017;389:2239–51.
 Rines AK, Sharabi K, Tavares CD, Puigserver P. Targeting hepatic glucose metabolism in the treatment of type 2 diabetes. Nat Rev Drug Discov 2016;15:786–804.
 Lee FY, Lee H, Hubbert ML, Edwards PA, Zhang Y. FXR, a multipurpose nuclear receptor. Trends Biochem Sci 2006;31:572-80.
 Renga B, Mencarelli A, D'Amore C, Cipriani S, Baldelli F, Zampella A, et al. Glucocorticoid receptor mediates the gluconeogenic activity ofthe farnesoid X receptor in the fasting condition. FASEB J 2012;26:3021-31.
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