Center of Drug Metabolism and Pharmacokinetics, College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Center of Drug Metabolism and Pharmacokinetics, College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Biochem Pharmacol. 2018 Apr;150:108-119. doi: 10.1016/j.bcp.2018.01.021. Epub 2018 Jan 13.
Skeletal muscle accounts for approximately 75% of glucose disposal in body and statins impair glucose metabolism. We aimed to investigate the effect of atorvastatin on glucose metabolism in C2C12 cells. Glucose metabolism and expression of glucose transporter 4 (GLUT4) and hexokinase II (HXKII) were measured following incubation with atorvastatin or pravastatin. Roles of cholesterol in atorvastatin-induced glucose metabolism impairment were investigated via adding cholesterol or mevalonic acid and confirmed by cholesterol depletion with methyl-β-cyclodextrin. Hypercholesterolemia mice induced by high fat diet (HFD) feeding, orally received atorvastatin (6 and 12 mg/kg) or pravastatin (12 mg/kg) for 22 days. Results showed that atorvastatin not pravastatin concentration-dependently impaired glucose consumption, glucose uptake and GLUT4 membrane translocation in C2C12 cells without affecting expression of HXKII or total GLUT4 protein. The atorvastatin-induced alterations were reversed by cholesterol or mevalonic acid. Cholesterol depletion exerted similar impact to atorvastatin, which could be alleviated by cholesterol supplement. Glucose consumption or GLUT4 translocation was positively associated with cellular cholesterol levels. In HFD mice, atorvastatin not pravastatin significantly increased blood glucose levels following glucose or insulin dose and decreased expression of membrane not total GLUT4 protein in muscle. Glucose exposure following glucose or insulin dose was negatively correlated to muscular free cholesterol concentration. Expression of membrane GLUT4 protein was positively related to free cholesterol in muscle. In conclusion, atorvastatin impaired glucose utilization in muscle cells partly via inhibiting GLUT4 membrane translocation due to inhibition of cholesterol synthesis by atorvastatin, at least, partly contributing to glucose intolerance in HFD mice.
骨骼肌约占身体葡萄糖摄取量的 75%，而他汀类药物会损害葡萄糖代谢。我们旨在研究阿托伐他汀对 C2C12 细胞葡萄糖代谢的影响。用阿托伐他汀或普伐他汀孵育后，测量葡萄糖代谢和葡萄糖转运蛋白 4 (GLUT4)和己糖激酶 II (HXKII)的表达。通过添加胆固醇或甲羟戊酸以及用甲基-β-环糊精耗竭胆固醇来研究胆固醇在阿托伐他汀诱导的葡萄糖代谢损伤中的作用，并通过胆固醇耗竭得到了证实。通过高脂饮食（HFD）喂养诱导高胆固醇血症小鼠，口服给予阿托伐他汀（6 和 12mg/kg）或普伐他汀（12mg/kg）22 天。结果表明，阿托伐他汀而非普伐他汀浓度依赖性地损害 C2C12 细胞中的葡萄糖消耗、葡萄糖摄取和 GLUT4 膜易位，而不影响 HXKII 或总 GLUT4 蛋白的表达。阿托伐他汀引起的变化可被胆固醇或甲羟戊酸逆转。胆固醇耗竭产生与阿托伐他汀相似的影响，可通过胆固醇补充缓解。葡萄糖消耗或 GLUT4 易位与细胞胆固醇水平呈正相关。在 HFD 小鼠中，与普伐他汀相比，阿托伐他汀显著增加葡萄糖或胰岛素剂量后的血糖水平，并降低肌肉中膜而不是总 GLUT4 蛋白的表达。葡萄糖或胰岛素剂量后的葡萄糖暴露与肌肉中游离胆固醇浓度呈负相关。膜 GLUT4 蛋白的表达与肌肉中的游离胆固醇呈正相关。总之，阿托伐他汀通过抑制胆固醇合成来损害葡萄糖的利用，至少部分导致 HFD 小鼠的葡萄糖不耐受，部分原因是抑制了 GLUT4 膜易位。
