Department of Pathology, Tulane University, New Orleans, Louisiana, USA.
Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
Hepatol Commun. 2024 Oct 30;8(11). doi: 10.1097/HC9.0000000000000564. eCollection 2024 Nov 1.
Extracellular matrix protein 1 (ECM1) can inhibit TGFβ activation, but its antifibrotic action remains largely unknown. This study aims to investigate ECM1 function and its physical interaction with the profibrotic connective tissue growth factor (CTGF) in fibrosis and ductular reaction (DR).
Ecm1 knockouts or animals that ectopically expressed this gene were subjected to induction of liver fibrosis and DR by feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or α-naphthyl-isothiocyanate (ANIT). ECM1 and CTGF were also examined in the livers of patients with alcohol-associated liver disease (ALD) or ethanol-exposed animals that were fed the western diet for 4 months in the WDA model with liver pathology resembing ALD in patients.
ECM1 bound to CTGF in yeast two-hybrid systems, cultured liver cells, and cholestatic livers damaged by DDC or α-naphthyl-isothiocyanate. This interaction blocked integrin αvβ6-mediated TGFβ activation, thereby reducing fibrotic responses in vitro. ECM1 downregulation was associated with biliary CTGF induction during human ALD progression. In experimental models, Ecm1 loss enhanced susceptibility to DDC-induced cholestasis with upregulation of Ctgf, αvβ6, alpha-smooth muscle actin, procollagen type I, serum transaminase, and total bilirubin levels in germline knockouts, whereas forced expression of this gene significantly attenuated DR and biliary fibrosis after the feeding of DDC or α-naphthyl-isothiocyanate containing diets. Moreover, ectopic Ecm1 inhibited not only alcohol-associated fibrosis but also TGFβ-mediated deregulation of hepatocyte nuclear factor 4α, preventing the production of the fetal p2 promoter-driven isoforms in the WDA model.
We uncover a novel antifibrotic action by ECM1 that binds CTGF and inhibits integrin αvβ6-mediated TGFβ activation. Targeting its loss has therapeutic potential for the treatment of DR and liver fibrosis in chronic conditions, such as cholangiopathy and ALD.
细胞外基质蛋白 1 (ECM1) 可以抑制 TGFβ 的激活，但它的抗纤维化作用在很大程度上尚不清楚。本研究旨在探讨 ECM1 功能及其与促纤维化结缔组织生长因子 (CTGF) 在纤维化和胆管反应 (DR) 中的物理相互作用。
采用 3,5-二乙氧基羰基-1,4-二氢吡啶 (DDC) 或α-萘基异硫氰酸酯 (ANIT) 喂养诱导肝纤维化和 DR，使 Ecm1 敲除或异位表达该基因的动物发生肝纤维化和 DR。还在酒精相关性肝病 (ALD) 患者的肝脏中以及在 WDA 模型中用 Western 饮食喂养 4 个月后暴露于乙醇的动物肝脏中检查 ECM1 和 CTGF，WDA 模型中的肝病理与患者的 ALD 相似。
ECM1 在酵母双杂交系统、培养的肝细胞和 DDC 或α-萘基异硫氰酸酯损伤的胆汁淤积性肝脏中与 CTGF 结合。这种相互作用阻断了整合素 αvβ6 介导的 TGFβ 激活，从而减少了体外的纤维化反应。在人类 ALD 进展过程中，ECM1 的下调与胆管 CTGF 的诱导有关。在实验模型中，Ecm1 缺失增强了 DDC 诱导的胆汁淤积易感性，导致 Ctgf、αvβ6、α-平滑肌肌动蛋白、I 型前胶原、血清转氨酶和总胆红素水平上调，而在 DDC 或α-萘基异硫氰酸酯喂养的饮食中强制表达该基因则显著减弱了 DR 和胆管纤维化。此外，异位 ECM1 不仅抑制了酒精相关性纤维化，还抑制了 TGFβ 介导的肝细胞核因子 4α 的失调，防止了 WDA 模型中胎儿 p2 启动子驱动的同工型的产生。
我们揭示了 ECM1 的一种新的抗纤维化作用，它与 CTGF 结合并抑制整合素 αvβ6 介导的 TGFβ 激活。针对其缺失可能为治疗慢性胆管病和 ALD 等情况下的 DR 和肝纤维化提供治疗潜力。
