Tyrosine Kinase receptor B (TrkB) attenuates liver fibrosis via inhibiting TGF beta/SMAD signaling

Liver fibrosis is a main indicator for increased mortality and long-term comorbidity in nonalcoholic steatohepatitis (NASH); and activation of hepatic stellate cells (HSC) and excessive deposition of extracellular matrix components are the hallmarks of liver fibrogenesis. Tropomyosin-related tyrosine kinase B (TrkB) is a multifunctional receptor participating in neurodegenerative disorders. However, paucity of literature is available about TrkB function in liver fibrosis. Herein, TrkB function and its regulatory network were explored in progression of hepatic fibrosis.Results: Protein levels of TrkB were decreased in NASH/CCl4-induced hepatic fibrosis mouse model. TrkB suppressed TGF beta-induced proliferation and activation in HSCs, and significantly repressed TGF beta/SMAD signaling pathway via directly interacting with SMAD2/3. TGF beta-induced Nedd4 family interacting protein-1 (Ndfip1) expression promoted the ubiquitination and degradation of TrkB via E3 ligase Nedd4-2. Moreover, AAV-medicated TrkB overexpression attenuated the extent of liver fibrosis in mouse models.