Atorvastatin Targets the Islet Mevalonate Pathway to Dysregulate mTOR Signaling and Reduce β-Cell Functional Mass
Atorvastatin Targets the Islet Mevalonate Pathway to Dysregulate mTOR Signaling and Reduce β-Cell Functional Mass
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阿托伐他汀靶向胰岛甲羟戊酸途径，调节 mTOR 信号传导并减少 β 细胞功能质量
DOI：
10.2337/db19-0178
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发表时间：
2020-01-01
期刊：
影响因子：
7.7
通讯作者：
Feng, Bo
中科院分区：
文献类型：
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作者：
Shen, Linyan;Gu, Yanyun;Feng, Bo
他汀类药物是降胆固醇药物，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）治疗的高脂饮食喂养的小鼠中，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）信号传导的机制靶基因和小G蛋白（sGP）基因的表达。补充甲羟戊酸途径中间体香叶基香叶基焦磷酸（GGPP）（由3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶产生）可显著恢复ator、洛伐他汀、瑞舒伐他汀和氟伐他汀治疗后减弱的mTOR活性、v-maf肌肉腱膜纤维肉瘤癌基因同源物A（MafA）表达和β细胞功能;该作用可能由sGP异戊二烯化介导。Rab 5a是受ator治疗影响最大的胰岛中的sGP，发现其正调节mTOR信号传导和β细胞功能。Rab 5a敲低模拟了ator处理对β细胞的作用。因此，ator通过调节sGP（例如Rab 5a）来损害β细胞功能，其随后减弱胰岛mTOR信号传导并减少功能性β细胞质量。GGPP补充剂可能构成预防他汀类药物诱导的高血糖症的新方法。
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.