Hypolipidemic effect of SIPI-7623,a derivative of an extract from oriental wormwood,through farnesoid X receptor antagonism  

作　　者：DENG Yi-Fang HUANG Xiao-Ling SU Mei YU Peng-Xia ZHANG Zhen LIU Quan-Hai WANG Guo-Ping LIU Min-Yu 

机构地区：[1]Department of Pharmacology,Shanghai Institute of Pharmaceutical Industry [2]Jiangsu Carephar Pharmaceutical Co.,Ltd.

出　　处：《Chinese Journal of Natural Medicines》2018年第8期572-579,共8页中国天然药物（英文版）

基　　金：supported by Shanghai Committee of Science and Technology(No.16431903500)

摘　　要：Farnesoid X receptor(FXR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors.As a metabolic regulator,FXR plays key roles in bile acid and cholesterol metabolism and lipid and glucose homeostasis.Therefore,FXR is a potential drug target for several metabolic syndromes,especially those related to lipidemia disorders.In the present study,we identified small molecule SIPI-7623,a derivative of an extract from Oriental wormwood(Artemisia capillaris),and found that it specifically upregulated the expression of cholesterol-7-alpha-hydroxylase(CYP7 A1),downregulated the expression of sterol-regulatory element-binding protein 1 c(SREBP-1 c) in the liver,and inhibited the expression of ileal bile acid binding-protein(IBABP) in the ileum of rats.We found that inhibition of FXR by SIPI-7623 decreased the level of cholesterol and triglyceride.SIPI-7623 reduced the levels of cholesterol and triglyceride in in vitro Hep G2 cell models,ameliorated diet-induced atherosclerosis,and decreased the serum lipid content on rats and rabbits model of atherosclerosis in vivo.Furthermore,SIPI-7623 decreased the extent of atherosclerotic lesions.Our resutls demonstrated that antagonism of the FXR pathway can be employed as a therapeutic strategy to treat metabolic diseases such as hyperlipidemia and atherosclerosis.In conclusion,SIPI-7623 could be a promising lead compound for development of drugs to treat hyperlipidemia and atherosclerosis.Farnesoid X receptor（FXR） is a member of the nuclear receptor superfamily of ligand-activated transcription factors.As a metabolic regulator,FXR plays key roles in bile acid and cholesterol metabolism and lipid and glucose homeostasis.Therefore,FXR is a potential drug target for several metabolic syndromes,especially those related to lipidemia disorders.In the present study,we identified small molecule SIPI-7623,a derivative of an extract from Oriental wormwood（Artemisia capillaris）,and found that it specifically upregulated the expression of cholesterol-7-alpha-hydroxylase（CYP7 A1）,downregulated the expression of sterol-regulatory element-binding protein 1 c（SREBP-1 c） in the liver,and inhibited the expression of ileal bile acid binding-protein（IBABP） in the ileum of rats.We found that inhibition of FXR by SIPI-7623 decreased the level of cholesterol and triglyceride.SIPI-7623 reduced the levels of cholesterol and triglyceride in in vitro Hep G2 cell models,ameliorated diet-induced atherosclerosis,and decreased the serum lipid content on rats and rabbits model of atherosclerosis in vivo.Furthermore,SIPI-7623 decreased the extent of atherosclerotic lesions.Our resutls demonstrated that antagonism of the FXR pathway can be employed as a therapeutic strategy to treat metabolic diseases such as hyperlipidemia and atherosclerosis.In conclusion,SIPI-7623 could be a promising lead compound for development of drugs to treat hyperlipidemia and atherosclerosis.

关 键 词：Farnesoid X receptor antagonist HYPOLIPIDEMIC Bile acid enterohepatic circulation Cholesterol-7-alpha-hydroxylase Sterol-regulatory element-binding protein 1c 

分 类 号：R965[医药卫生—药理学]