Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.
Shanghai Institute of Liver Diseases, Shanghai, China.
Hepatology. 2023 Nov 1;78(5):1433-1447. doi: 10.1097/HEP.0000000000000319. Epub 2023 Feb 22.
Liver fibrosis is a leading indicator for increased mortality and long-term comorbidity in NASH. Activation of HSCs and excessive extracellular matrix production are the hallmarks of liver fibrogenesis. Tyrosine kinase receptor (TrkB) is a multifunctional receptor that participates in neurodegenerative disorders. However, paucity of literature is available about TrkB function in liver fibrosis. Herein, the regulatory network and therapeutic potential of TrkB were explored in the progression of hepatic fibrosis.
The protein level of TrkB was decreased in mouse models of CDAHFD feeding or carbon tetrachloride-induced hepatic fibrosis. TrkB suppressed TGF-β-stimulated proliferation and activation of HSCs in 3-dimensional liver spheroids and significantly repressed TGF-β/SMAD signaling pathway either in HSCs or in hepatocytes. The cytokine, TGF-β, boosted Nedd4 family interacting protein-1 (Ndfip1) expression, promoting the ubiquitination and degradation of TrkB through E3 ligase Nedd4-2. Moreover, carbon tetrachloride intoxication-induced hepatic fibrosis in mouse models was reduced by adeno-associated virus vector serotype 6 (AAV6)-mediated TrkB overexpression in HSCs. In addition, in murine models of CDAHFD feeding and Gubra-Amylin NASH (GAN), fibrogenesis was reduced by adeno-associated virus vector serotype 8 (AAV8)-mediated TrkB overexpression in hepatocytes.
TGF-β stimulated TrkB degradation through E3 ligase Nedd4-2 in HSCs. TrkB overexpression inhibited the activation of TGF-β/SMAD signaling and alleviated the hepatic fibrosis both in vitro and in vivo . These findings demonstrate that TrkB could be a significant suppressor of hepatic fibrosis and confer a potential therapeutic target in hepatic fibrosis.
肝纤维化是 NASH 患者死亡率增加和长期合并症的主要指标。HSCs 的激活和细胞外基质的过度产生是肝纤维化发生的标志。酪氨酸激酶受体（TrkB）是一种多功能受体，参与神经退行性疾病。然而，关于 TrkB 在肝纤维化中的作用的文献很少。本文探讨了 TrkB 在肝纤维化进展中的调控网络和治疗潜力。
在 CDAHFD 喂养或四氯化碳诱导的肝纤维化小鼠模型中，TrkB 的蛋白水平降低。TrkB 抑制了 3D 肝球体中 TGF-β 刺激的 HSCs 的增殖和激活，并显著抑制了 HSCs 或肝细胞中 TGF-β/SMAD 信号通路。细胞因子 TGF-β 促进了 Nedd4 家族相互作用蛋白-1（Ndfip1）的表达，通过 E3 连接酶 Nedd4-2 促进了 TrkB 的泛素化和降解。此外，通过 HSCs 中的腺相关病毒载体血清型 6（AAV6）介导的 TrkB 过表达，减少了小鼠模型中四氯化碳中毒诱导的肝纤维化。此外，在 CDAHFD 喂养和 Gubra-胰岛淀粉样多肽 NASH（GAN）的小鼠模型中，通过肝细胞中的腺相关病毒载体血清型 8（AAV8）介导的 TrkB 过表达，减少了纤维化的发生。
TGF-β 通过 HSCs 中的 E3 连接酶 Nedd4-2 刺激 TrkB 的降解。TrkB 过表达抑制了 TGF-β/SMAD 信号的激活，并在体内外减轻了肝纤维化。这些发现表明，TrkB 可能是肝纤维化的重要抑制因子，并为肝纤维化提供了一个潜在的治疗靶点。
