Glial cell line‐derived neurotrophic factor contributes to alcoholic‐induced liver injury by regulating the NF‐κB pathway

• Published in: Alcoholism, clinical and experimental research Vol. 46; no. 5; pp. 724 - 735
• Main Authors: Liu, Xuling, Yang, Guangyue, Sun, Tiantian, Tao, Le, Shen, Dongxiao, Zhang, Wei, Zhang, Jie, Xue, Dongying, Chen, Bei, Wu, Liu, Liu, Cheng, Ma, Wenting
• Format: Journal Article
• Language: English
• Published: England 01.05.2022
• Subjects: ALD; Animals; Chemical and Drug Induced Liver Injury, Chronic - metabolism; Cytokines - metabolism; Disease Models, Animal; Ethanol - adverse effects; GDNF; Glial Cell Line-Derived Neurotrophic Factor - metabolism; Glial Cell Line-Derived Neurotrophic Factor - therapeutic use; Humans; Inflammation - metabolism; Liver - metabolism; Liver Diseases, Alcoholic - metabolism; Mice; Mice, Inbred C57BL; NF-kappa B - metabolism; NF‐κB; RNA, Messenger - metabolism; GDNF; NF-κB; ALD
• ISSN: 0145-6008; 1530-0277; 1530-0277
• DOI: 10.1111/acer.14815

Background Alcoholic liver disease (ALD) is associated with high morbidity and mortality worldwide. The pathogenesis of ALD is not completely understood. Although accumulating evidence suggests an important role of glial cell line‐derived neurotrophic factor (GDNF) in several diseases, there are no data concerning its role in ALD. This study compared patients with ALD with control subjects and used a mouse model and a cell culture model to investigate the function of GDNF in ALD and its mechanism of action in hepatocyte injury. Methods Serum levels of GDNF were measured in 25 patients with ALD and 25 healthy control subjects. A 4‐week Lieber–DeCarli ethanol (EtOH) liquid diet combined with the Gao–Binge model was used in the mouse study. Mouse primary hepatocytes and Huh‐7 cells were used for cell experiments. The parameters of liver injury, inflammatory cytokines, and lipid metabolism were measured. Results Patients with alcoholic hepatitis had higher serum GDNF than control subjects. Expression of GDNF mRNA and protein was markedly increased in mice in the chronic‐plus‐binge ALD mouse model. The level of GDNF mRNA was upregulated in primary hepatic stellate cells isolated from ethanol‐fed mouse liver. Ethanol induced GDNF expression in LX2 cells. The levels of inflammatory cytokines (tumor necrosis factor α, interleukin 1β, and monocyte chemotactic protein 1) were significantly increased after GDNF stimulation in primary hepatocytes and Huh‐7 cells. After GDNF stimulation, levels of both p‐AKT and p‐NF‐κB were significantly increased in primary hepatocytes and Huh‐7 cells. The NF‐κB activity induced by GDNF was significantly decreased by an NF‐κB inhibitor, which limited hepatocyte injury and inflammation. Conclusions The concentration of GDNF is increased in the circulation of ALD patients. GDNF promotes alcohol‐induced liver injury and inflammation via the activation of NF‐κB, which mediates hepatocyte injury and inflammatory cytokine expression. Based on these findings, GDNF is a potential therapeutic target for preventing or ameliorating liver injury in ALD. Serum GDNF levels were significantly higher in patients with alcoholic liver disease (ALD) compared with healthy controls. Alcohol‐mediated GDNF up‐regulation was confirmed in vivo and in vitro. Hepatic stellate cells mainly express GDNF in a mouse model of ALD. GDNF‐induced inflammation was observed in primary hepatocytes. This work suggests GDNF promotes alcohol‐induced liver injury via the activation of NF‐κB.