한국발생생물학회지:발생과생식 (Development and Reproduction)

  • 제27권2호
  • /
  • Pages.77-89
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  • 2023
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  • 2465-9525(pISSN)
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  • 2465-9541(eISSN)
한국발생생물학회 (The Korean Society of Developmental Biology)
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Metformin Induces Lipogenesis and Apoptosis in H4IIE Hepatocellular Carcinoma Cells

  • Deokbae Park (Department of Histology, Jeju National University College of Medicine) ;
  • Sookyoung Lee (Department of Histology, Jeju National University College of Medicine) ;
  • Hyejin Boo (Department of Histology, Jeju National University College of Medicine)
  • 투고 : 2023.04.11
  • 심사 : 2023.06.15
  • 발행 : 2023.06.30
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초록

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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과제정보

This work was supported by the 2023 education, research and student guidance grant funded by Jeju National University.

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