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Systemic TM4SF5 overexpression in ApcMin/+ mice promotes hepatic portal hypertension associated with fibrosis
Joohyeong Lee 1,2 (Graduate student), Eunmi Kim 1,2 (Research Professor), Min-Kyung Kang1 (Research Worker), Jihye Ryu1 (Research Worker), Ji Eon Kim 1 (Postdoc), Eun-Ae Shin 1 (Graduate student), Yangie Pinanga 1 (Graduate student), Kyung-hee Pyo 1 (Graduate student), Haesong Lee 1 (Graduate student), Eun Hae Lee 1 (Graduate student), Heejin Cho 1 (Graduate student), Jayeon Cheon 1 (Graduate student), Wonsik Kim 1 (Graduate student), Eek-Hoon Jho1 (Professor), Jung Weon Lee 1,2,* (Professor)
1Department of Pharmacy and 2Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea (Republic of),
3Department of Life Science, University of Seoul, Seoul 02504, Korea (Republic of),
4Microbiome Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejon 34141, Korea (Republic of)
Abstract
Mutation of the gene for adenomatous polyposis coli (APC), as seen in ApcMin/+ mice, leads to intestinal adenomas and carcinomas via stabilization of モ-catenin. Transmembrane 4 L six family member 5 (TM4SF5) is known to be involved in the development of non-alcoholic fatty liver disease, fibrosis, and cancer. However, the functional linkage between TM4SF5 and APC or モ-catenin has not been investigated for pathological outcomes. After interbreeding ApcMin/+ with TM4SF5-overexpressing transgenic (TgTM4SF5) mice, pathological outcomes in the intestines and livers of the offspring were explored. 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 led to increased stabilization of モ-catenin via reduced glycogen synthase kinase 3モ (GSK3モ) phosphorylation on Ser9. Additionally, the livers of the dual-transgenic mice showed distinct sinusoidal dilatation and features of hepatic portal hypertension associated with fibrosis, compared to the relatively normal livers in ApcMin/+ mice. Interestingly, TM4SF5 overexpression in the liver was positively linked to increased GSK3モ phosphorylation (opposite that seen in the colon), モ-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 both in the colon and the liver.
Abstract, Accepted Manuscript(in press) [Submitted on June 27, 2022, Accepted on August 30, 2022]
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