RT Journal Article
SR Electronic
T1 Glial cell line-derived neurotrophic factor (GDNF) mediates hepatic stellate cell activation via ALK5/Smad signalling
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 2214
OP 2227
DO 10.1136/gutjnl-2018-317872
VO 68
IS 12
A1 Tao, Le
A1 Ma, Wenting
A1 Wu, Liu
A1 Xu, Mingyi
A1 Yang, Yanqin
A1 Zhang, Wei
A1 Sha, Wenjun
A1 Li, Hongshan
A1 Xu, Jianrong
A1 Feng, Rilu
A1 Xue, Dongying
A1 Zhang, Jie
A1 Dooley, Steven
A1 Seki, Ekihiro
A1 Liu, Ping
A1 Liu, Cheng
YR 2019
UL http://gut.bmj.com/content/68/12/2214.abstract
AB Objective Although glial cell line-derived neurotrophic factor (GDNF) is a member of the transforming growth factor-β superfamily, its function in liver fibrosis has rarely been studied. Here, we investigated the role of GDNF in hepatic stellate cell (HSC) activation and liver fibrosis in humans and mice.Design GDNF expression was examined in liver biopsies and sera from patients with liver fibrosis. The functional role of GDNF in liver fibrosis was examined in mice with adenoviral delivery of the GDNF gene, GDNF sgRNA CRISPR/Cas9 and the administration of GDNF-blocking antibodies. GDNF was examined on HSC activation using human and mouse primary HSCs. The binding of activin receptor-like kinase 5 (ALK5) to GDNF was determined using surface plasmon resonance (SPR), molecular docking, mutagenesis and co-immunoprecipitation.Results GDNF mRNA and protein levels are significantly upregulated in patients with stage F4 fibrosis. Serum GDNF content correlates positively with α-smooth muscle actin (α-SMA) and Col1A1 mRNA in human fibrotic livers. Mice with overexpressed GDNF display aggravated liver fibrosis, while mice with silenced GDNF expression or signalling inhibition by GDNF-blocking antibodies have reduced fibrosis and HSC activation. GDNF is confined mainly to HSCs and contributes to HSC activation through ALK5 at His39 and Asp76 and through downstream signalling via Smad2/3, but not through GDNF family receptor alpha-1 (GFRα1). GDNF, ALK5 and α-SMA colocalise in human and mouse HSCs, as demonstrated by confocal microscopy.Conclusions GDNF promotes HSC activation and liver fibrosis through ALK5/Smad signalling. Inhibition of GDNF could be a novel therapeutic strategy to combat liver fibrosis.