Systemic TM4SF5 overexpression in Apc^Min/+ mice promotes hepatic portal hypertension associated with fibrosis

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 (Tg TM4SF5 ) mice, we explored pathological outcomes in the intestines and livers of the offspring. The intestines of 26-week-old dual-transgenic mice (Apc Min/+ :Tg TM4SF5 ) had intramucosal adenocarcinomas beyond the single-crypt adenomas in Apc Min/+ 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 Apc Min/+ 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 Tg TM4SF5 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. [BMB Reports 2022; 55(12): 609-614]

Renalase Prevents Renal Fibrosis by Inhibiting Endoplasmic Reticulum Stress and Down-Regulating GSK-3β/Snail Signaling

“…Currently, the reported actions of GSK-3β in organ fibrosis are inconsistent. In liver fibrosis, activation of GSK-3β may improve insulin and leptin resistance in the liver, thereby improving liver fibrosis 12 ; however, the increase of GSK-3β expression may promote the progression of liver fibrosis 13 , 14 . In pulmonary fibrosis, sinensetin can activate GSK-3β to reduce pulmonary fibrosis 15 , but inhibition of GSK-3β can also improve pulmonary fibrosis 16 , 17 .…”

TM4SF5-mediated abnormal food-intake behavior and apelin expression facilitate non-alcoholic fatty liver disease features

“… 20 TM4SF5 is involved in the development of NAFLD 21 and portal hypertension. 22 Bidirectional TM4SF5-dependent crosstalks between hepatocytes and macrophages lead to the polarization and reprogramming of macrophages in chronic inflammatory environments to develop NASH-associated fibrosis. 23 Under high-fat, carbohydrate, or fructose diets, TM4SF5-overexpressing mice show obesity and NASH-like phenotypes compared to TM4SF5-knockout mice.…”