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Atorvastatin Targets the Islet Mevalonate Pathway to Dysregulate mTOR Signaling and Reduce β-cell Functional Mass
Diabetes ( IF 7.7 ) Pub Date : 2019-10-24 , DOI: 10.2337/db19-0178
Linyan Shen 1 , Yanyun Gu 2 , Yixuan Qiu 3 , Tingting Cheng 1 , Aifang Nie 3 , Canqi Cui 3 , Chenyang Fu 3 , Tingting Li 3 , Xuelin Li 3 , Lihong Fu 3 , Yanqiu Wang 3 , Qicheng Ni 3 , Qidi Wang 3 , Weiqing Wang 3 , Bo Feng 4
Affiliation  

Statins are cholesterol-lowering agents that increase the incidence of diabetes and impair glucose tolerance via their detrimental effects on nonhepatic tissues, such as pancreatic islets, but the underlying mechanism has not been determined. In atorvastatin (ator)-treated high-fat diet–fed mice, we found reduced pancreatic β-cell size and β-cell mass, fewer mature insulin granules, and reduced insulin secretion and glucose tolerance. Transcriptome profiling of primary pancreatic islets showed that ator inhibited the expression of pancreatic transcription factor, mechanistic target of rapamycin (mTOR) signaling, and small G protein (sGP) genes. Supplementation of the mevalonate pathway intermediate geranylgeranyl pyrophosphate (GGPP), which is produced by 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, significantly restored the attenuated mTOR activity, v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) expression, and β-cell function after ator, lovastatin, rosuvastatin, and fluvastatin treatment; this effect was potentially mediated by sGP prenylation. Rab5a, the sGP in pancreatic islets most affected by ator treatment, was found to positively regulate mTOR signaling and β-cell function. Rab5a knockdown mimicked the effect of ator treatment on β-cells. Thus, ator impairs β-cell function by regulating sGPs, for example, Rab5a, which subsequently attenuates islet mTOR signaling and reduces functional β-cell mass. GGPP supplementation could constitute a new approach for preventing statin-induced hyperglycemia.

中文翻译:

阿托伐他汀靶向胰岛甲羟戊酸途径以失调 mTOR 信号并减少 β 细胞功能质量

他汀类药物是降低胆固醇的药物,通过对非肝组织(如胰岛)的有害作用增加糖尿病的发病率并损害葡萄糖耐量,但其潜在机制尚未确定。在阿托伐他汀 (ator) 处理的高脂肪饮食喂养的小鼠中,我们发现胰腺 β 细胞大小和 β 细胞质量减少,成熟胰岛素颗粒减少,胰岛素分泌和葡萄糖耐量降低。原代胰岛的转录组分析表明,ator 抑制胰腺转录因子、雷帕霉素 (mTOR) 信号转导机制靶标和小 G 蛋白 (sGP) 基因的表达。补充由 3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶产生的甲羟戊酸途径中间体香叶基香叶基焦磷酸(GGPP),在 ator、洛伐他汀、瑞舒伐他汀和氟伐他汀治疗后,显着恢复了减弱的 mTOR 活性、v-maf 肌肉腱膜纤维肉瘤癌基因同源物 A (MafA) 的表达和 β 细胞功能;这种效应可能是由 sGP 异戊二烯化介导的。Rab5a 是胰岛中受 ator 治疗影响最大的 sGP,被发现可正向调节 mTOR 信号传导和 β 细胞功能。Rab5a 敲低模拟了 ator 处理对 β 细胞的影响。因此,ator 通过调节 sGPs 来损害 β 细胞功能,例如 Rab5a,随后减弱胰岛 mTOR 信号并减少功能性 β 细胞质量。GGPP 补充剂可以构成一种预防他汀类药物引起的高血糖的新方法。洛伐他汀、瑞舒伐他汀和氟伐他汀治疗;这种效应可能是由 sGP 异戊二烯化介导的。Rab5a 是胰岛中受 ator 治疗影响最大的 sGP,被发现可正向调节 mTOR 信号传导和 β 细胞功能。Rab5a 敲低模拟了 ator 处理对 β 细胞的影响。因此,ator 通过调节 sGPs 来损害 β 细胞功能,例如 Rab5a,随后减弱胰岛 mTOR 信号并减少功能性 β 细胞质量。GGPP 补充剂可以构成一种预防他汀类药物引起的高血糖的新方法。洛伐他汀、瑞舒伐他汀和氟伐他汀治疗;这种效应可能是由 sGP 异戊二烯化介导的。Rab5a 是胰岛中受 ator 治疗影响最大的 sGP,被发现可正向调节 mTOR 信号传导和 β 细胞功能。Rab5a 敲低模拟了 ator 处理对 β 细胞的影响。因此,ator 通过调节 sGPs 来损害 β 细胞功能,例如 Rab5a,随后减弱胰岛 mTOR 信号并减少功能性 β 细胞质量。GGPP 补充剂可以构成一种预防他汀类药物引起的高血糖的新方法。Rab5a 敲低模拟了 ator 处理对 β 细胞的影响。因此,ator 通过调节 sGPs 来损害 β 细胞功能,例如 Rab5a,随后减弱胰岛 mTOR 信号并减少功能性 β 细胞质量。GGPP 补充剂可以构成一种预防他汀类药物引起的高血糖的新方法。Rab5a 敲低模拟了 ator 处理对 β 细胞的影响。因此,ator 通过调节 sGPs 来损害 β 细胞功能,例如 Rab5a,随后减弱胰岛 mTOR 信号并减少功能性 β 细胞质量。GGPP 补充剂可以构成一种预防他汀类药物引起的高血糖的新方法。
更新日期:2019-10-24
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