With the high prevalence of obesity, diabetes, and otherfeatures of the metabolic syndrome in United States, nonalcoholic fatty liver disease(NAFLD) has inevitably become a very prevalent chronic liver disease and is ...With the high prevalence of obesity, diabetes, and otherfeatures of the metabolic syndrome in United States, nonalcoholic fatty liver disease(NAFLD) has inevitably become a very prevalent chronic liver disease and is now emerging as one of the leading indications for liver transplantation. Insulin resistance and derangement of lipid metabolism, accompanied by activation of the pro-inflammatory response and fibrogenesis, are essential pathways in the development of the more clinically significant form of NAFLD, known as nonalcoholic steatohepatitis(NASH). Recent advances in the functional characterization of bile acid receptors, such as farnesoid X receptor(FXR) and transmembrane G protein-coupled receptor(TGR) 5, have provided further insight in the pathophysiology of NASH and have led to the development of potential therapeutic targets for NAFLD and NASH. Beyond maintaining bile acid metabolism, FXR and TGR5 also regulate lipid metabolism, maintain glucose homeostasis, increase energy expenditure, and ameliorate hepatic inflammation. These intriguing features have been exploited to develop bile acid analogues to target pathways in NAFLD and NASH pathogenesis. This review provides a brief overview of the pathogenesis of NAFLD and NASH, and then delves into the biological functions of bile acid receptors, particularly with respect to NASH pathogenesis, with a description of the associated experimental data, and, finally, we discuss the prospects of bile acid analogues in the treatment of NAFLD and NASH.展开更多
目的ATP结合盒B亚家族成员1(ATP binding cassette subfamily B member 1,ABCB1)的异常表达在多种癌症的发生发展中发挥关键作用。然而,G蛋白偶联受体C家族5组A型(G protein coupled receptor family C group5 type A,GPRC5A)调控的ABCB...目的ATP结合盒B亚家族成员1(ATP binding cassette subfamily B member 1,ABCB1)的异常表达在多种癌症的发生发展中发挥关键作用。然而,G蛋白偶联受体C家族5组A型(G protein coupled receptor family C group5 type A,GPRC5A)调控的ABCB1表达对肺腺癌增殖的影响仍不清楚。本研究探讨了GPRC5A调控的ABCB1表达对肺腺癌增殖的影响。方法我们采用RT-PCR、Western-blot或免疫组化实验,分析ABCB1在肺腺癌细胞系、人肺腺癌组织以及GPRC5A基因敲除小鼠和野生型小鼠的气管上皮细胞和肺组织中的表达。采用细胞计数试剂盒-8(CCK-8)分析GPRC5A基因敲除小鼠气管上皮细胞对化疗药物的敏感性。采用皮下肿瘤形成实验探讨下调ABCB1表达是否可抑制体内肺腺癌增殖。采用免疫荧光和免疫沉淀实验研究GPRC5A和ABCB1之间潜在的调控关系。结果ABCB1在肺腺癌细胞系和人类肺腺癌组织中表达上调。GPRC5A基因敲除小鼠的气管上皮细胞及肺组织的ABCB1表达高于野生型小鼠。与GPRC5A野生型小鼠的气管上皮细胞相比,GPRC5A基因敲除小鼠的气管上皮细胞对塔立奇达和多柔比星更敏感。注射移植细胞28天后,接受ABCB1基因敲除细胞移植的GPRC5A-/-C57BL/6小鼠的肺肿瘤的体积和重量均明显低于野生型细胞移植小鼠(P=0.0043,P=0.0060)。此外,免疫荧光和免疫沉淀实验表明,GPRC5A通过直接结合方式调控ABCB1的表达。结论GPRC5A通过抑制ABCB1表达降低肺腺癌增殖。GPRC5A调节ABCB1表达的途径有待研究。展开更多
文摘With the high prevalence of obesity, diabetes, and otherfeatures of the metabolic syndrome in United States, nonalcoholic fatty liver disease(NAFLD) has inevitably become a very prevalent chronic liver disease and is now emerging as one of the leading indications for liver transplantation. Insulin resistance and derangement of lipid metabolism, accompanied by activation of the pro-inflammatory response and fibrogenesis, are essential pathways in the development of the more clinically significant form of NAFLD, known as nonalcoholic steatohepatitis(NASH). Recent advances in the functional characterization of bile acid receptors, such as farnesoid X receptor(FXR) and transmembrane G protein-coupled receptor(TGR) 5, have provided further insight in the pathophysiology of NASH and have led to the development of potential therapeutic targets for NAFLD and NASH. Beyond maintaining bile acid metabolism, FXR and TGR5 also regulate lipid metabolism, maintain glucose homeostasis, increase energy expenditure, and ameliorate hepatic inflammation. These intriguing features have been exploited to develop bile acid analogues to target pathways in NAFLD and NASH pathogenesis. This review provides a brief overview of the pathogenesis of NAFLD and NASH, and then delves into the biological functions of bile acid receptors, particularly with respect to NASH pathogenesis, with a description of the associated experimental data, and, finally, we discuss the prospects of bile acid analogues in the treatment of NAFLD and NASH.
文摘目的ATP结合盒B亚家族成员1(ATP binding cassette subfamily B member 1,ABCB1)的异常表达在多种癌症的发生发展中发挥关键作用。然而,G蛋白偶联受体C家族5组A型(G protein coupled receptor family C group5 type A,GPRC5A)调控的ABCB1表达对肺腺癌增殖的影响仍不清楚。本研究探讨了GPRC5A调控的ABCB1表达对肺腺癌增殖的影响。方法我们采用RT-PCR、Western-blot或免疫组化实验,分析ABCB1在肺腺癌细胞系、人肺腺癌组织以及GPRC5A基因敲除小鼠和野生型小鼠的气管上皮细胞和肺组织中的表达。采用细胞计数试剂盒-8(CCK-8)分析GPRC5A基因敲除小鼠气管上皮细胞对化疗药物的敏感性。采用皮下肿瘤形成实验探讨下调ABCB1表达是否可抑制体内肺腺癌增殖。采用免疫荧光和免疫沉淀实验研究GPRC5A和ABCB1之间潜在的调控关系。结果ABCB1在肺腺癌细胞系和人类肺腺癌组织中表达上调。GPRC5A基因敲除小鼠的气管上皮细胞及肺组织的ABCB1表达高于野生型小鼠。与GPRC5A野生型小鼠的气管上皮细胞相比,GPRC5A基因敲除小鼠的气管上皮细胞对塔立奇达和多柔比星更敏感。注射移植细胞28天后,接受ABCB1基因敲除细胞移植的GPRC5A-/-C57BL/6小鼠的肺肿瘤的体积和重量均明显低于野生型细胞移植小鼠(P=0.0043,P=0.0060)。此外,免疫荧光和免疫沉淀实验表明,GPRC5A通过直接结合方式调控ABCB1的表达。结论GPRC5A通过抑制ABCB1表达降低肺腺癌增殖。GPRC5A调节ABCB1表达的途径有待研究。
