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Gut. 2019 Dec;68(12):2214-2227. doi: 10.1136/gutjnl-2018-317872. Epub 2019 Jun 6.

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

Tao L#1,2, Ma W#2, Wu L#2, Xu M#3, Yang Y4, Zhang W1, Sha W5, Li H6, Xu J7, Feng R8, Xue D2, Zhang J2, Dooley S8, Seki E9, Liu P10,11, Liu C1,2,12.

Author information

1
Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
2
Laboratory of Liver Disease, Department of Infectious Disease, PutuoHospital , Shanghai University of Traditional Chinese Medicine, Shanghai, China.
3
Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4
Department of Pathology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
5
Departmentof Endocrinology and Metabolism, PutuoHospital , Shanghai University of Traditional Chinese Medicine, Shanghai, China.
6
Department of Hepatology, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China.
7
Department of Pharmacology and Chemical Biology, Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
8
Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
9
Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
10
Shanghai University of Traditional Chinese Medicine, Shanghai, China.
11
Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
12
Shanghai Putuo Central School of Clinical Medicine, Anhui Medical University, Shanghai, China.
#
Contributed equally

Abstract

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.

KEYWORDS:

chronic liver disease; hepatic fibrosis; hepatic stellate cell

PMID:
31171625
PMCID:
PMC6842044
DOI:
10.1136/gutjnl-2018-317872
[Indexed for MEDLINE]
Free PMC Article

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