Park Deokbae, Lee Sookyoung, Boo Hyejin
Department of Histology, Jeju National University College of Medicine, Jeju 63243, Korea.
Dev Reprod. 2023 Jun;27(2):77-89. doi: 10.12717/DR.2023.27.2.77. Epub 2023 Jun 30.
Metformin is the most widely used anti-diabetic drug that helps maintain normal blood glucose levels primarily by suppressing hepatic gluconeogenesis in type II diabetic patients. We previously found that metformin induces apoptotic death in H4IIE rat hepatocellular carcinoma cells. Despite its anti-diabetic roles, the effect of metformin on hepatic de novo lipogenesis (DNL) remains unclear. We investigated the effect of metformin on hepatic DNL and apoptotic cell death in H4IIE cells. Metformin treatment stimulated glucose consumption, lactate production, intracellular fat accumulation, and the expressions of lipogenic proteins. It also stimulated apoptosis but reduced autophagic responses. These metformin-induced changes were clearly reversed by compound C, an inhibitor of AMP-activated protein kinase (AMPK). Interestingly, metformin massively increased the production of reactive oxygen species (ROS), which was completely blocked by compound C. Metformin also stimulated the phosphorylation of p38 mitogen-activated protein kinase (p38MAPK). Finally, inhibition of p38MAPK mimicked the effects of compound C, and suppressed the metformin-induced fat accumulation and apoptosis. Taken together, metformin stimulates dysregulated glucose metabolism, intracellular fat accumulation, and apoptosis. Our findings suggest that metformin induces excessive glucose-induced DNL, oxidative stress by ROS generation, activation of AMPK and p38MAPK, suppression of autophagy, and ultimately apoptosis.
二甲双胍是应用最广泛的抗糖尿病药物，主要通过抑制II型糖尿病患者的肝糖异生来帮助维持正常血糖水平。我们之前发现二甲双胍可诱导H4IIE大鼠肝癌细胞发生凋亡性死亡。尽管二甲双胍具有抗糖尿病作用，但其对肝脏从头脂肪生成（DNL）的影响仍不清楚。我们研究了二甲双胍对H4IIE细胞肝脏DNL和凋亡性细胞死亡的影响。二甲双胍处理可刺激葡萄糖消耗、乳酸生成、细胞内脂肪积累以及脂肪生成蛋白的表达。它还刺激细胞凋亡，但减少自噬反应。这些二甲双胍诱导的变化被AMP激活的蛋白激酶（AMPK）抑制剂化合物C明显逆转。有趣的是，二甲双胍大量增加活性氧（ROS）的产生，而这被化合物C完全阻断。二甲双胍还刺激p38丝裂原活化蛋白激酶（p38MAPK）的磷酸化。最后，抑制p38MAPK模拟了化合物C的作用，并抑制了二甲双胍诱导的脂肪积累和细胞凋亡。综上所述，二甲双胍刺激失调的葡萄糖代谢、细胞内脂肪积累和细胞凋亡。我们的研究结果表明，二甲双胍诱导过度的葡萄糖诱导的DNL、通过ROS生成引起的氧化应激、AMPK和p38MAPK的激活、自噬的抑制，并最终导致细胞凋亡。
