二甲双胍（metformin）是最广泛使用的抗糖尿病药物，主要通过抑制肝脏糖异生来维持Ⅱ型糖尿病患者的正常血糖水平。我们之前发现，二甲双胍可以诱导H4IIE大鼠肝细胞癌细胞凋亡死亡。尽管其具有抗糖尿病的作用，但二甲双胍对肝脏新生脂肪合成（DNL）的影响仍不清楚。我们研究了二甲双胍对H4IIE细胞中肝脏DNL和细胞凋亡死亡的影响。二甲双胍处理刺激了葡萄糖消耗、乳酸产生、细胞内脂肪积累以及脂肪合成蛋白的表达。它还刺激了细胞凋亡，但减少了自噬反应。这些二甲双胍诱导的变化明显地被AMP激活的蛋白激酶（AMPK）抑制剂compound C逆转。有趣的是，二甲双胍大量增加了活性氧生成物（ROS）的产生，该过程被compound C完全阻断。此外，二甲双胍还刺激了p38线粒体活化蛋白激酶（p38MAPK）的磷酸化。最后，抑制p38MAPK的作用与compound C的作用相似，可以抑制二甲双胍诱导的脂肪积累和细胞凋亡。综上所述，二甲双胍刺激了失调的葡萄糖代谢、细胞内脂肪积累和细胞凋亡。我们的发现表明，二甲双胍通过过量的葡萄糖诱导的DNL、ROS生成的氧化应激、AMPK和p38MAPK的激活、自噬的抑制以及最终的细胞凋亡的发生。Copyright © 2023 The Korean Society of Developmental Biology.

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.Copyright © 2023 The Korean Society of Developmental Biology.