Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates.
Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.
Endocrine. 2022 Jun;76(3):543-557. doi: 10.1007/s12020-022-03022-x. Epub 2022 Mar 2.
Metformin (MF) intake associates with reduced levels of circulating low-density lipoprotein-cholesterol (LDL-C). This has been attributed to the activation of AMPK, which differentially regulates the expression of multiple genes involved in cholesterol synthesis and trafficking. However, the exact mechanism underlying the LDL-C lowering effect of MF remains ambiguous.
MF-treated Hep-G2 and HuH7 cells were evaluated for cell viability and the expression status of key lipid metabolism-related genes along with LDL-C uptake efficiency.
MF treatment resulted in decreased expression and secretion of PCSK9, increased expression of LDLR and enhanced LDL-C uptake in hepatocytes. It also resulted in increased expression of activated AMPK (p-AMPK) and decreased expression of SREBP2 and HNF-1α proteins. Transcriptomic analysis of MF-treated Hep-G2 cells confirmed these findings and showed that other key lipid metabolism-related genes including those that encode apolipoproteins (APOB, APOC2, APOC3 and APOE), MTTP and LIPC are downregulated. Lastly, MF treatment associated with reduced HMG-CoA reductase expression and activity.
These findings suggest that MF treatment reduces circulating LDL-C levels by suppressing PCSK9 expression and enhancing LDLR expression; hence the potential therapeutic utility of MF in hypercholesterolemia.
二甲双胍（MF）的摄入与循环中低密度脂蛋白胆固醇（LDL-C）水平的降低有关。这归因于 AMPK 的激活，它可差异调节参与胆固醇合成和转运的多个基因的表达。然而，MF 降低 LDL-C 作用的确切机制仍不清楚。
评估 MF 处理的 Hep-G2 和 HuH7 细胞的细胞活力以及关键脂质代谢相关基因的表达状态以及 LDL-C 摄取效率。
MF 处理导致 PCSK9 的表达和分泌减少，LDLR 的表达增加，肝细胞中 LDL-C 的摄取增加。它还导致激活的 AMPK（p-AMPK）的表达增加和 SREBP2 和 HNF-1α 蛋白的表达减少。MF 处理的 Hep-G2 细胞的转录组分析证实了这些发现，并表明其他关键脂质代谢相关基因，包括编码载脂蛋白（APOB、APOC2、APOC3 和 APOE）、MTTP 和 LIPC 的基因也下调。最后，MF 治疗与 HMG-CoA 还原酶表达和活性降低有关。
这些发现表明，MF 治疗通过抑制 PCSK9 的表达和增强 LDLR 的表达来降低循环中的 LDL-C 水平；因此，MF 在高胆固醇血症中的潜在治疗用途。
