New Insight Into Metformin-Induced Cholesterol-Lowering Effect Crosstalk Between Glucose and Cholesterol Homeostasis via ChREBP (Carbohydrate-Responsive Element-Binding Protein)-Mediated PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Regulation
New Insight Into Metformin-Induced Cholesterol-Lowering Effect Crosstalk Between Glucose and Cholesterol Homeostasis via ChREBP (Carbohydrate-Responsive Element-Binding Protein)-Mediated PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Regulation
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通过 ChREBP（碳水化合物响应元件结合蛋白）介导的 PCSK9（前蛋白转化酶枯草杆菌蛋白酶/Kexin 9 型）对二甲双胍诱导的血糖和胆固醇稳态之间的串扰有了新的见解
DOI：
10.1161/atvbaha.120.315708
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发表时间：
2021-04-01
影响因子：
8.7
通讯作者：
Peng, Daoquan
中科院分区：
文献类型：
--
作者：
Hu, Die;Guo, Yanhong;Peng, Daoquan
目的：二甲双胍是治疗 2 型糖尿病的一线药物，具有降胆固醇作用，但其确切机制尚未确定。方法和结果：在 2 个血脂异常小鼠模型中，二甲双胍给药显着降低血清胆固醇和 PCSK9（前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型）水平，并伴有 PCSK9 表达下降 mRNA 和蛋白质水平导致肝脏中 LDLR（低密度脂蛋白受体）增加 3 倍。在人肝细胞中，二甲双胍治疗抑制了 PCSK9 转录。转录抑制是由葡萄糖传感器 ChREBP（碳水化合物响应元件结合蛋白）驱动的，而不是由细胞内胆固醇传感器 SREBP2（甾醇调节元件结合蛋白 2）驱动的。我们进一步确定 PCSK9 为 ChREBP 的新靶基因。二甲双胍可降低 ChREBP 的表达，并通过阻断其核转位来抑制其转录活性，而这种转位归因于细胞内葡萄糖和葡萄糖代谢物水平的降低。此外，二甲双胍治疗显着降低了非糖尿病个体的血清低密度脂蛋白胆固醇和 PCSK9 水平。结论：总的来说，我们揭示了二甲双胍降低胆固醇的新作用机制，并通过 ChREBP 介导的 PCSK9 调节确定了葡萄糖和胆固醇稳态之间的新串扰信号。
Objective:Metformin, a first-line drug for treating individuals with type 2 diabetes, exerts beneficial effects on cholesterol-lowering, yet its precise mechanism has not been established.Approach and Results:In 2 dyslipidemia mouse models, administration of metformin significantly decreased serum cholesterol and PCSK9 (proprotein convertase subtilisin/kexin type 9) levels, accompanied by decreased expression of PCSK9 in both mRNA and protein levels resulting in a 3-fold increase of LDLR (low-density lipoprotein receptor) in the liver. In human hepatocytes, metformin treatment suppressed the PCSK9 transcription. Depressed transcription was driven by a glucose sensor, the ChREBP (carbohydrate-responsive element-binding protein) but not by the intracellular cholesterol sensor, the SREBP2 (sterol regulatory element-binding protein 2). We further identified PCSK9 as a novel target gene of ChREBP. Metformin decreased the expression of ChREBP and inhibited its transcriptional activity by blocking its nuclear translocation attributed to the decreased intracellular glucose and glucose metabolites levels. Moreover, metformin treatment significantly decreased serum low-density lipoprotein cholesterol and PCSK9 levels in nondiabetic individuals.Conclusions:Collectively, we revealed a new mechanism of action of metformin in cholesterol-lowering and identified a novel crosstalk signal between glucose and cholesterol homeostasis via ChREBP-mediated PCSK9 regulation.