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
Die Hu, Yanhong Guo, Renrong Wu, Tiannan Shao, Junke Long, Bilian Yu, Huilun Wang, Yonghong Luo, Haocheng Lu, Jifeng Zhang, Y. Eugene Chen, Daoquan Peng
Abstract
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.