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Discovery of Novel FXR Ligands and Study of Their Function on Lipid Metabolism Regulation

Author: YuYing
Tutor: ShenXu
School: East China University of Science and Technology
Course: Biochemistry and Molecular Biology
Keywords: farnesoid X receptor (FXR) antagonist partial agonist lowering-lipid thermogenic genes
CLC: R966
Type: Master's thesis
Year: 2012
Downloads: 120
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The farnesoid X receptor (FXR) is an important ligand-activated transcriptional factor. More and more studies demonstrated that FXR antagonists play critical roles in treating hypercholesterolemia. However, few effective FXR antagonists have been found so far, mainly deriving from steroidal scaffold. In this study, we employed structure and ligand-based virtual screening combining with biophysics, cell biology and chemical systhesis technologies to find a novel FXR antagonist-compound12u. The antagonistic activity and the ability of lowering cholesterol and triglyceride of compound12u are much better than Guggulsterole (GS). In addition, we discovered that compound12u lowered cholesterol and triglyceride mainly through regulating SHP and CYP7A1gene expression..Recently, it has been reported that SHP knockout or CYP7A1over-expression mice have the tendency to protect against diet-induced obesity and diabetes through increasing energy expenditure. Compound12u could strongly inhibit SHP gene expression and increase CYP7A1gene expression, we thus conducted the mechanism study of compound12u on increasing the thermogenic genes in brown fat cells.Previous studies have shown that FXR agonists can lower the level of lipid and glucose. However, the treatment of GW4064for the long-term can induce C57BL/6J mice fed with high-fat diet obesity and diabetes. We thus synthesized an FXR partial agonist-compound PD0384, which included the structures of GW4064and compound12u. We compared the effects of compound PD0384and GW4064on the thermogenic genes expression in brown fat cells. The experimental results showed that compound PD0384could increase the expression of thermogenic genes, but GW4064failed to increase the expression of these genes. Meanwhile, we also found that compound PD0384could reverse the inhibitory effect of GW4064on thermogenic genes. It was suggested that compound PD0384could improve the side effects of GW4064and have a potential application in treating obesity.

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