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
Plasma lipids are controlled by genes and play an important role in the development of atherosclerosis. Dysplipidemia is an important risk factor for coronary artery disease (CAD). Coronary artery disease is the leadi...Plasma lipids are controlled by genes and play an important role in the development of atherosclerosis. Dysplipidemia is an important risk factor for coronary artery disease (CAD). Coronary artery disease is the leading cause of mortality and morbidity in the developed world. More than 14 million Americans are afflicted with clinically significant CAD.~1 To illustrate the impact of CAD in developed countries, the medical and societal costs of CAD in the United States alone are in excess of $90 billion annually.~1 More than (600 000) Americans each year develop new cardiac events, more than 10% of which occur in Americans (<50) years of age.~1 Identifying genetic predisposition to early onset of CAD could help in understanding basic disease mechanism, guiding targeted preventive efforts, and planning appropriate therapeutic strategies.展开更多
文摘目的:探讨胆固醇结石(GS)小鼠肝脏的核受体基因——肝核受体类似物1(liver receptor homolog 1,LRH-1)及其调控基因胆固醇7α-羟化酶(cholesterol 7-αhydroxylase,CYP7A1)的表达。方法:雌性C57BL/6小鼠40只,分为2组,每组20只,分别予以正常饮食、高脂饮食喂养10周后处死。病理切片检查小鼠胆囊壁细胞组织学改变,实时定量PCR法测定肝脏LRH-1及CYP7A1表达量。Western Blot方法测定肝脏上述基因蛋白的表达量。结果:胆结石小鼠胆囊壁细胞呈现炎性改变。胆石组小鼠LRH-1 m RNA及蛋白表达均高于对照组(P<0.01),CYP7A1 m RNA及蛋白表达量较对照组升高(P<0.01)。结论:啮齿动物肝脏LRH-1和CYP7A1的表达异常与胆囊胆固醇结石形成有关,可能共同在小鼠胆结石形成中发挥作用。
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.
文摘Plasma lipids are controlled by genes and play an important role in the development of atherosclerosis. Dysplipidemia is an important risk factor for coronary artery disease (CAD). Coronary artery disease is the leading cause of mortality and morbidity in the developed world. More than 14 million Americans are afflicted with clinically significant CAD.~1 To illustrate the impact of CAD in developed countries, the medical and societal costs of CAD in the United States alone are in excess of $90 billion annually.~1 More than (600 000) Americans each year develop new cardiac events, more than 10% of which occur in Americans (<50) years of age.~1 Identifying genetic predisposition to early onset of CAD could help in understanding basic disease mechanism, guiding targeted preventive efforts, and planning appropriate therapeutic strategies.
