Tyrosine kinase receptor B attenuates liver fibrosis by inhibiting TGF-β/SMAD signaling

Abstract

Background and Aims: 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. Methods and Results: 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. Conclusion: 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.

Secretome of senescent hepatic stellate cells favors malignant transformation from nonalcoholic steatohepatitis-fibrotic progression to hepatocellular carcinoma

“…3D liver spheroids were constructed with activated (BSCC-10 cells for the control group) or senescent (BSCC-10 cells passaging to F30 for the senescent group) HSCs and rat primary cells in 384-well Corning as reported previously 25 . Both cell types were assembled with DNA origamis in a ratio of 1:1 (3000 cells per spheroid).…”

NEDD4 and NEDD4L: Ubiquitin Ligases Closely Related to Digestive Diseases

“…Recently, Yu Song et al found that TGF-β1 could induce NEDD4 family-interacting protein 1 (Ndfip1) to promote the degradation of TrkB via UPS, thereby promoting the progression of liver fibrosis. Thus, TrkB is expected to be a novel therapeutic target for liver fibrosis, which opens up a new way of thinking about the treatment of liver fibrosis [155].…”

Interdisciplinary advances reshape the delivery tools for effective NASH treatment

“…However, the potential of upregulating the expression of genes that suppress the onset and progression of NASH has not been fully appreciated, which is complementary to the RNAi strategy. Recent studies have indicated activation of glutathione S-transferase Mu 2 [ 138 ], tyrosine kinase receptor B [ 139 ], dual specificity phosphatase 22, etc [ 140 ] attenuates the progression of NASH. Besides the aforementioned mRNA-LNP strategy that delivers HGF mRNA into hepatocytes, can investigators use non-coding RNA to activate the expression of NASH suppressors?…”