Β-catenin/TCF4 inhibitors ICG-001 and LF3 alleviate BDL-induced liver fibrosis by suppressing LECT2 signaling. (1st February 2023)

• Record Type: Journal Article
• Authors: Gao, Yue; Fan, Shicheng; Zhao, Pengfei; Li, Huilin; Cai, Chenghui; Li, Xuan; Zhou, Yanying; Huang, Min; Bi, Huichang
• Is Part Of: Chemico-biological interactions. Volume 371(2023)
• Publication Date: 2023-02-01
• Subjects: Leukocyte cell-derived chemotaxin 2 -- β-catenin/TCF4 signaling -- Liver fibrosis -- Angiogenesis -- Bile duct ligation; aHSCs activated hepatic stellate cells -- ALP alkaline phosphatase -- ALT alanine aminotransferase -- α-SMA α-smooth muscle actin -- AST aspartate aminotransferase -- BDL bile duct ligation -- CBP CREB binding protein -- CD31 platelet and endothelial cell adhesion molecule 1 -- ECM extracellular matrix -- γ-GT gamma-glutamyl transpeptidase -- H&E hematoxylin and eosin -- LECT2 leukocyte cell-derived chemotaxin 2 -- LEF lymphoid enhancer-binding factor -- LSECs liver sinusoidal endothelial cells -- LYVE1 lymphatic endothelial receptor-1 -- MMPs matrix metalloproteinases -- qHSCs quiescent hepatic stellate cells -- TBA total bile acids -- TBIL total bilirubin -- TCF T cell-specific factor -- TIMPs tissue inhibitors of metalloproteinases; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2023.110350
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: Liver fibrosis can be characterized by the over-deposition of extracellular matrix (ECM). It has been reported that β-catenin/TCF4 interaction was enhanced in bile duct ligation (BDL) model, which implicated the critical role of β-catenin/TCF4 interaction during the progression of fibrosis. However, whether inhibiting β-catenin/TCF4 signaling attenuates liver fibrosis remains unknown. In the current study, we used ICG-001, an inhibitor that disrupts the interaction between CREB binding protein (CBP) and β-catenin, to inhibit β-catenin/TCF4 transcriptional activity. We also used LF3, a small molecule antagonist, to inhibit β-catenin/TCF4 interaction. The antifibrotic effect of ICG-001 and LF3 was assessed on BDL-induced liver fibrosis model. The results indicated both ICG-001 and LF3 significantly reduced the positive staining area of Sirius Red and α-SMA. The protein expression levels of α-SMA, Collagen Ⅰ and CD31 were also significantly downregulated in BDL + ICG-001 and BDL + LF3 groups. Besides, ICG-001 and LF3 promoted portal angiogenesis and inhibited sinusoids capillarization in fibrotic livers. For mechanistic study, we measured the level of leukocyte cell-derived chemotaxin 2 (LECT2), a direct target of β-catenin/TCF4, which was recently reported to participate in hepatic fibrosis by regulating angiogenesis. The results showed that both ICG-001 and LF3 reduced LECT2 expression in BDL mice. LF3 also downregulated pSer 675 β-catenin and nuclear β-catenin. In conclusion, this study demonstrated that inhibiting β-catenin/TCF4 signaling by ICG-001 or LF3 mitigated liver fibrosis by downregulating LECT2, promoting portal angiogenesis and inhibiting sinusoids capillarization, which provided new evidence that β-catenin/TCF4 signaling might be a target for the treatment of liver fibrosis. Graphical abstract: The inhibition of β-catenin/TCF4 signaling by ICG-001 or LF3 alleviated hepatic fibrosis in BDL model. Further study demonstrated that ICG-001 and LF3 downregulated LECT2 expression to promote portal angiogenesis and inhibit sinusoids capillarization simultaneously, which suggested that disrupting β-catenin/TCF4 interaction might be a new therapeutic approach for liver fibrosis. Image 1 Highlights: β-catenin/TCF4 inhibitors ICG-001 and LF3 mitigates BDL-induced liver fibrosis. Both ICG-001 and LF3 promotes portal angiogenesis and inhibits sinusoids capillarization in fibrotic livers. ICG-001 and LF3 inhibits LECT2 expression in fibrotic livers without affecting β-catenin expression.