Z Gastroenterol 2019; 57(09): e244
DOI: 10.1055/s-0039-1695260
Leber und Galle
Tiermodelle für ACLF, Leberregeneration, Karzinogenese, Leberfribrose: Donnerstag, 03. Oktober 2019, 11:05 – 12:41, Studio Terrasse 2.1 A
Georg Thieme Verlag KG Stuttgart · New York

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

R Feng
1   Sektion Molecular Hepatology, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Deutschland
,
L Tao
2   Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
3   Laboratory of liver disease, Department of Infectious Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
,
W Ma
3   Laboratory of liver disease, Department of Infectious Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
,
L Wu
3   Laboratory of liver disease, Department of Infectious Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
,
E Seki
4   Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, Vereinigte Staaten von Amerika
,
C Liu
2   Central Laboratory, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
3   Laboratory of liver disease, Department of Infectious Disease, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
,
S Dooley
1   Sektion Molecular Hepatology, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Deutschland
› Author Affiliations
Further Information

Publication History

Publication Date:
13 August 2019 (online)

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    Objective:

    Although glial cell line-derived neurotrophic factor (GDNF) is a member of the transforming growth factor-β (TGFβ) 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 upon 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 coimmunoprecipitation.

    Results:

    GDNF mRNA and protein levels are significantly upregulated in patients with stage F4 fibrosis. Serum GDNF content correlates positively with α-SMA and Col1A1 mRNA in human fibrotic livers. Mice with overexpressed GDNF display aggravated liver fibrosis, while mice with silenced GDNF expression or signaling 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 signaling via Smad2/3, but not through GDNF family receptor alpha-1 (GFRα1). GDNF, ALK5, and α-SMA colocalize in human and mouse HSCs, as demonstrated by confocal microscopy.

    Conclusions:

    GDNF promotes HSC activation and liver fibrosis through ALK5/Smad signaling. Inhibition of GDNF could be a novel therapeutic strategy to combat liver fibrosis.


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