Involvement of pregnane X receptor in the impaired glucose utilization induced by atorvastatin in hepatocytes
Involvement of pregnane X receptor in the impaired glucose utilization induced by atorvastatin in hepatocytes
复制标题
孕烷X受体参与阿托伐他汀引起的肝细胞葡萄糖利用受损
DOI：
10.1016/j.bcp.2015.11.023
复制
发表时间：
2016-01-15
影响因子：
5.8
通讯作者：
Liu, Xiaodong
中科院分区：
文献类型：
--
作者：
Ling, Zhaoli;Shu, Nan;Liu, Xiaodong
越来越多的证据表明，他汀类药物损害了葡萄糖的利用。本研究旨在探讨PXR是否参与阿托伐他汀受损的葡萄糖利用。以利福平/PCN为PXR激活剂对照。检测细胞葡萄糖利用率、葡萄糖摄取率、GLUT2、GCK、PDK2、PEPCK1和G6Pase的蛋白水平。应用PXR抑制剂、PXR过表达和PXR siRNA验证PXR在阿托伐他汀损伤的细胞葡萄糖利用中的作用。高脂饮食诱导的高胆固醇血症大鼠，口服阿托伐他汀(5 mg/kg和10 mg/kg)、普伐他汀(10 mg/kg)14d，或腹腔注射PCN(35 mg/kg)4d。结果显示阿托伐他汀、辛伐他汀、匹伐他汀、洛伐他汀和利福平对葡萄糖利用有明显的抑制作用。瑞舒伐他汀和普伐他汀都没有显示出类似的效果。阿托伐他汀和普伐他汀被选为后续研究。阿托伐他汀和利福平显著抑制葡萄糖摄取，下调GLUT2和GCK的表达。同样，过表达PXR显著下调GLUT2和GCK的表达，并损害葡萄糖的利用。酮康唑和白藜芦醇可减轻阿托伐他汀和利福平对亲代和高表达PXR细胞葡萄糖利用的损害。PXR基因敲除显著上调GLUT2和GCK蛋白表达，并阻断阿托伐他汀和利福平减少的葡萄糖消耗和摄取。动物实验表明，阿托伐他汀和PCN显著诱导餐后高血糖，导致血糖AUC增加。阿托伐他汀和PCN可显著下调大鼠肝脏GLUT2和GCK的表达。总之，阿托伐他汀通过抑制GLUT2和GCK的表达来损害肝细胞的葡萄糖利用，这可能部分是由于PXR的激活。(C)2015 Elsevier Inc.保留所有权利。
Accumulating evidences demonstrated that statins impaired glucose utilization. This study was aimed to investigate whether PXR was involved in the atorvastatin-impaired glucose utilization. Rifampicin/PCN served as PXR activator control. Glucose utilization, glucose uptake, protein levels of GLUT2, GCK, PDK2, PEPCK1 and G6Pase in HepG2 cells were measured. PXR inhibitors, PXR overexpression and PXR siRNA were applied to verify the role of PXR in atorvastatin-impaired glucose utilization in cells. Hypercholesterolemia rats induced by high fat diet feeding, orally received atorvastatin (5 and 10 mg/kg), pravastatin (10 mg/kg) for 14 days, or intraperitoneally received PCN (35 mg/kg) for 4 days. Results showed that glucose utilization was markedly inhibited by atorvastatin, simvastatin, pitavastatin, lovastatin and rifampicin. Neither rosuvastatin nor pravastatin showed the similar effect. Atorvastatin and pravastatin were selected for the following study. Atorvastatin and rifampicin significantly inhibited glucose uptake and down-regulated GLUT2 and GCK expressions. Similarly, overexpressed PXR significantly down-regulated GLUT2 and GCK expressions and impaired glucose utilization. Ketoconazole and resveratrol attenuated the impaired glucose utilization by atorvastatin and rifampicin in both parental and overexpressed PXR cells. PXR knockdown significantly up-regulated GLUT2 and GCK proteins and abolished the decreased glucose consumption and uptake by atorvastatin and rifampicin. Animal experiments showed that atorvastatin and PCN significantly elicited postprandial hyperglycemia, leading to increase in glucose AUC. Expressions of GLUT2 and GCK in rat livers were markedly down regulated by atorvastatin and PCN. In conclusion, atorvastatin impaired glucose utilization in hepatocytes via repressing GLUT2 and GCK expressions, which may be partly due to PXR activation. (C) 2015 Elsevier Inc. All rights reserved.