Metformin Induces Lipogenesis and Apoptosis in H4IIE Hepatocellular Carcinoma Cells.

Development & reproduction Pub Date : 2023-06-01 Epub Date: 2023-06-30 DOI:10.12717/DR.2023.27.2.77
Deokbae Park, Sookyoung Lee, Hyejin Boo
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Abstract

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.

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二甲双胍诱导 H4IIE 肝细胞癌细胞的脂肪生成和凋亡
二甲双胍是最广泛使用的抗糖尿病药物,主要通过抑制 II 型糖尿病患者的肝糖生成来帮助维持正常血糖水平。我们以前曾发现二甲双胍能诱导 H4IIE 大鼠肝癌细胞凋亡。尽管二甲双胍具有抗糖尿病作用,但它对肝脏新生脂肪生成(DNL)的影响仍不清楚。我们研究了二甲双胍对肝脏DNL和H4IIE细胞凋亡的影响。二甲双胍治疗刺激了葡萄糖消耗、乳酸生成、细胞内脂肪积累以及脂肪生成蛋白的表达。二甲双胍还刺激细胞凋亡,但减少了自噬反应。二甲双胍诱导的这些变化被化合物 C(一种 AMP 激活蛋白激酶(AMPK)抑制剂)明显逆转。有趣的是,二甲双胍会大量增加活性氧(ROS)的产生,而化合物 C 能完全阻断活性氧的产生。二甲双胍还会刺激 p38 丝裂原活化蛋白激酶(p38MAPK)的磷酸化。最后,抑制 p38MAPK 可模拟化合物 C 的作用,并抑制二甲双胍诱导的脂肪堆积和细胞凋亡。综上所述,二甲双胍会刺激糖代谢失调、细胞内脂肪堆积和细胞凋亡。我们的研究结果表明,二甲双胍会诱导过度葡萄糖诱导的 DNL、通过 ROS 生成氧化应激、激活 AMPK 和 p38MAPK、抑制自噬并最终导致细胞凋亡。
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