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 gl...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.展开更多
基金supported by Shanghai Committee of Science and Technology(No.16431903500)
文摘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.
