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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Mettl14 mutation restrains liver regeneration by attenuating mitogens derived from non-parenchymal liver cells

  • Insook, Yang (Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Seoul National University) ;
  • Seung Yeon, Oh (Korea Mouse Phenotyping Center (KMPC), Seoul National University) ;
  • Suin, Jang (Korea Mouse Phenotyping Center (KMPC), Seoul National University) ;
  • Il Yong, Kim (Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Seoul National University) ;
  • You Me, Sung (Korea Mouse Phenotyping Center (KMPC), Seoul National University) ;
  • Je Kyung, Seong (Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Seoul National University)
  • Received : 2022.09.13
  • Accepted : 2022.10.24
  • Published : 2022.12.31
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Abstract

Liver regeneration is a well-known systemic homeostatic phenomenon. The N6-methyladenosine (m6A) modification pathway has been associated with liver regeneration and hepatocellular carcinoma. m6A methyltransferases, such as methyltransferase 3 (METTL3) and methyltransferase 14 (METTL14), are involved in the hepatocyte-specific-regenerative pathway. To illustrate the role of METTL14, secreted from non-parenchymal liver cells, in the initiation phase of liver regeneration, we performed 70% partial hepatectomy (PH) in Mettl14 heterozygous (HET) and wild-type (WT) mice. Next, we analyzed the ratio of liver weight to body weight and the expression of mitogenic stimulators derived from non-parenchymal liver cells. Furthermore, we evaluated the expression of cell cycle-related genes and the hepatocyte proliferation rate via MKI67-immunostaining. During regeneration after PH, the weight ratio was lower in Mettl14 HET mice compared to WT mice. The expressions of hepatocyte growth factor (HGF) and tumor necrosis factor (TNF)-α, mitogens derived from non-parenchymal liver cells that stimulate the cell cycle, as well as the expressions of cyclin B1 and D1, which regulate the cell cycle, and the number of MKI67-positive cells, which indicate proliferative hepatocyte in the late G1-M phase, were significantly reduced in Mettl14 HET mice 72 h after PH. Our findings demonstrate that global Mettl14 mutation may interrupt the homeostasis of liver regeneration after an acute injury like PH by restraining certain mitogens, such as HGF and TNF-α, derived from sinusoidal endothelial cells, stellate cells, and Kupffer cells. These results provide new insights into the role of METTL14 in the clinical treatment strategies of liver disease.

Keywords

Acknowledgement

This research was supported by Korea Mouse Phenotyping Project (2013M3A9D5072550) of the National Research Foundation funded by the Ministry of Science and ICT (2012M3A9D1054622) and partially supported by the Brain Korea 21 Plus Program and the Research Institute for Veterinary Science of Seoul National University.

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