Glial cell line-derived neurotrophic factor (GDNF) mediates hepatic stellate cell activation via ALK5/Smad signalling

被引：54

作者：

Tao, Le ^{[1
,2
]}

Ma, Wenting ^{[2
]}

Wu, Liu ^{[2
]}

Xu, Mingyi ^{[3
]}

Yang, Yanqin ^{[4
]}

Zhang, Wei ^{[1
]}

Sha, Wenjun ^{[5
]}

Li, Hongshan ^{[6
]}

Xu, Jianrong ^{[7
]}

Feng, Rilu ^{[8
]}

Xue, Dongying ^{[2
]}

Zhang, Jie ^{[2
]}

Dooley, Steven ^{[8
]}

Seki, Ekihiro ^{[9
]}

Liu, Ping ^{[10
,11
]}

Liu, Cheng ^{[1
,2
,12
]}

机构：

[1] Shanghai Univ Tradit Chinese Med, Putuo Hosp, Cent Lab, Shanghai 200062, Peoples R China

[2] Shanghai Univ Tradit Chinese Med, Putuo Hosp, Dept Infect Dis, Lab Liver Dis, Shanghai 200062, Peoples R China

[3] Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Dept Gastroenterol, Sch Med, Shanghai, Peoples R China

[4] Shanghai Univ Tradit Chinese Med, Putuo Hosp, Dept Pathol, Shanghai, Peoples R China

[5] Shanghai Univ Tradit Chinese Med, Dept Endocrinol & Metab, Putuo Hosp, Shanghai, Peoples R China

[6] Univ Chinese Acad Sci, HwaMei Hosp, Dept Hepatol, Ningbo, Peoples R China

[7] Shanghai Jiao Tong Univ, Dept Pharmacol & Chem Biol, Fac Basic Med, Sch Med, Shanghai, Peoples R China

[8] Heidelberg Univ, Med Fac Mannheim, Dept Med 2, Mannheim, Germany

[9] Cedars Sinai Med Ctr, Dept Med, Div Digest & Liver Dis, Los Angeles, CA 90048 USA

[10] Shanghai Univ Tradit Chinese Med, Shanghai, Peoples R China

[11] Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Inst Liver Dis, Shanghai, Peoples R China

[12] Anhui Med Univ, Shanghai Putuo Cent Sch Clin Med, Shanghai, Peoples R China

来源：

GUT | 2019年 / 68卷 / 12期

基金：

美国国家卫生研究院; 中国国家自然科学基金;

关键词：

TGF-BETA; LIVER FIBROSIS; RECEPTOR; GFR-ALPHA-1; INFLAMMATION; STAGE; GENE; MICE;

D O I：

10.1136/gutjnl-2018-317872

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Objective Although glial cell line-derived neurotrophic factor (GDNF) is a member of the transforming growth factor-beta 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 alpha-smooth muscle actin (alpha-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 His(39) and Asp(76) and through downstream signalling via Smad2/3, but not through GDNF family receptor alpha-1 (GFR alpha 1). GDNF, ALK5 and alpha-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.

引用

页码：2214 / 2227

页数：14

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