Systemic TM4SF5 overexpression in ApcMin/+ mice promotes hepatic portal hypertension associated with fibrosis
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Mutation of the gene for adenomatous polyposis coli (APC), asseen in ApcMin/+ mice, leads to intestinal adenomas and carcinomasvia stabilization of β-catenin. Transmembrane 4 L sixfamily member 5 (TM4SF5) is involved in the development ofnon-alcoholic fatty liver disease, fibrosis, and cancer. However,the functional linkage between TM4SF5 and APC or β-cateninhas not been investigated for pathological outcomes. After interbreedingApcMin/+ with TM4SF5-overexpressing transgenic(TgTM4SF5) mice, we explored pathological outcomes in the intestinesand livers of the offspring. The intestines of 26-week-olddual-transgenic mice (ApcMin/+:TgTM4SF5) had intramucosal adenocarcinomasbeyond the single-crypt adenomas in ApcMin/+ mice. Additional TM4SF5 overexpression increased the stabilizationof β-catenin via reduced glycogen synthase kinase 3β (GSK3β)phosphorylation on Ser9. Additionally, the livers of the dualtransgenicmice showed distinct sinusoidal dilatation and featuresof hepatic portal hypertension associated with fibrosis,more than did the relatively normal livers in ApcMin/+ mice. Interestingly, TM4SF5 overexpression in the liver was positivelylinked to increased GSK3β phosphorylation (opposite to thatseen in the colon), β-catenin level, and extracellular matrix (ECM)protein expression, indicating fibrotic phenotypes. Consistentwith these results, 78-week-old TgTM4SF5 mice similarly had sinusoidaldilatation, immune cell infiltration, and fibrosis. Altogether,systemic overexpression of TM4SF5 aggravates pathologicalabnormalities in both the colon and the liver.
Abstract
Mutation of the gene for adenomatous polyposis coli (APC), asseen in ApcMin/+ mice, leads to intestinal adenomas and carcinomasvia stabilization of β-catenin. Transmembrane 4 L sixfamily member 5 (TM4SF5) is involved in the development ofnon-alcoholic fatty liver disease, fibrosis, and cancer. However,the functional linkage between TM4SF5 and APC or β-cateninhas not been investigated for pathological outcomes. After interbreedingApcMin/+ with TM4SF5-overexpressing transgenic(TgTM4SF5) mice, we explored pathological outcomes in the intestinesand livers of the offspring. The intestines of 26-week-olddual-transgenic mice (ApcMin/+:TgTM4SF5) had intramucosal adenocarcinomasbeyond the single-crypt adenomas in ApcMin/+ mice. Additional TM4SF5 overexpression increased the stabilizationof β-catenin via reduced glycogen synthase kinase 3β (GSK3β)phosphorylation on Ser9. Additionally, the livers of the dualtransgenicmice showed distinct sinusoidal dilatation and featuresof hepatic portal hypertension associated with fibrosis,more than did the relatively normal livers in ApcMin/+ mice. Interestingly, TM4SF5 overexpression in the liver was positivelylinked to increased GSK3β phosphorylation (opposite to thatseen in the colon), β-catenin level, and extracellular matrix (ECM)protein expression, indicating fibrotic phenotypes. Consistentwith these results, 78-week-old TgTM4SF5 mice similarly had sinusoidaldilatation, immune cell infiltration, and fibrosis. Altogether,systemic overexpression of TM4SF5 aggravates pathologicalabnormalities in both the colon and the liver.
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