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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Systemic TM4SF5 overexpression in ApcMin/+ mice promotes hepatic portal hypertension associated with fibrosis

  • Joohyeong, Lee (Department of Pharmacy College of Pharmacy, Seoul National University) ;
  • Eunmi, Kim (Department of Pharmacy College of Pharmacy, Seoul National University) ;
  • Min-Kyung, Kang (Department of Pharmacy College of Pharmacy, Seoul National University) ;
  • Jihye, Ryu (Department of Pharmacy College of Pharmacy, Seoul National University) ;
  • Ji Eon, Kim (Department of Pharmacy College of Pharmacy, Seoul National University) ;
  • Eun-Ae, Shin (Department of Pharmacy College of Pharmacy, Seoul National University) ;
  • Yangie, Pinanga (Department of Pharmacy College of Pharmacy, Seoul National University) ;
  • Kyung-hee, Pyo (Department of Pharmacy College of Pharmacy, Seoul National University) ;
  • Haesong, Lee (Department of Pharmacy College of Pharmacy, Seoul National University) ;
  • Eun Hae, Lee (Department of Pharmacy College of Pharmacy, Seoul National University) ;
  • Heejin, Cho (Department of Pharmacy College of Pharmacy, Seoul National University) ;
  • Jayeon, Cheon (Department of Pharmacy College of Pharmacy, Seoul National University) ;
  • Wonsik, Kim (Department of Pharmacy College of Pharmacy, Seoul National University) ;
  • Eek-Hoon, Jho (Department of Life Science, University of Seoul) ;
  • Semi, Kim (Microbiome Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Jung Weon, Lee (Department of Pharmacy College of Pharmacy, Seoul National University)
  • Received : 2022.06.27
  • Accepted : 2022.08.30
  • Published : 2022.12.31
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Abstract

Mutation of the gene for adenomatous polyposis coli (APC), as seen in ApcMin/+ mice, leads to intestinal adenomas and carcinomas via stabilization of β-catenin. Transmembrane 4 L six family member 5 (TM4SF5) is involved in the development of non-alcoholic fatty liver disease, fibrosis, and cancer. However, the functional linkage between TM4SF5 and APC or β-catenin has not been investigated for pathological outcomes. After interbreeding ApcMin/+ with TM4SF5-overexpressing transgenic (TgTM4SF5) mice, we explored pathological outcomes in the intestines and livers of the offspring. The intestines of 26-week-old dual-transgenic mice (ApcMin/+:TgTM4SF5) had intramucosal adenocarcinomas beyond the single-crypt adenomas in ApcMin/+ mice. Additional TM4SF5 overexpression increased the stabilization of β-catenin via reduced glycogen synthase kinase 3β (GSK3β) phosphorylation on Ser9. Additionally, the livers of the dualtransgenic mice showed distinct sinusoidal dilatation and features of hepatic portal hypertension associated with fibrosis, more than did the relatively normal livers in ApcMin/+ mice. Interestingly, TM4SF5 overexpression in the liver was positively linked to increased GSK3β phosphorylation (opposite to that seen in the colon), β-catenin level, and extracellular matrix (ECM) protein expression, indicating fibrotic phenotypes. Consistent with these results, 78-week-old TgTM4SF5 mice similarly had sinusoidal dilatation, immune cell infiltration, and fibrosis. Altogether, systemic overexpression of TM4SF5 aggravates pathological abnormalities in both the colon and the liver.

Keywords

Acknowledgement

This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2020R1I1A1A01070020 to EMK, NRF-2021R1A6A3A01087300 to JEK, NRF-2018M3A9C8020027, NRF-2020R1A2C3008993, and NRF-2021M3A9D3024752 to JWL).

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