RAGE promotes dysregulation of iron and lipid metabolism in alcoholic liver disease

• Published in: Redox biology 2023-02, Vol.59, p.102559-102559, Article 102559
• Main Authors: Li, Yunjia, Qin, Mengchen, Zhong, Weichao, Liu, Chang, Deng, Guanghui, Yang, Menghan, Li, Junjie, Ye, Haixin, Shi, Hao, Wu, Chaofeng, Lin, Haiyan, Chen, Yuyao, Huang, Shaohui, Zhou, Chuying, Lv, Zhiping, Gao, Lei
• Format: Article
• Language: English
• Subjects: Animals; Ethanol; Ferritins - metabolism; Hepcidins - genetics; Inflammation; Iron - metabolism; Lipid Metabolism; Lipid peroxidation; Liver - metabolism; Liver Diseases, Alcoholic - metabolism; Macrophages; Mice; Oxidative stress; RAGE; Receptor for Advanced Glycation End Products - metabolism; Research Paper; Transferrin - metabolism
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2022.102559

Alcoholic liver disease (ALD) is associated with hepatic inflammatory activation and iron overload. The receptor for advanced glycation end products (RAGE) is an important metabolic mediator during the development of ALD. The aim of this study was to determine the effect of RAGE on iron homeostasis in ALD. We found increased circulating transferrin, hepcidin and ferritin in ALD patients and positively correlated with RAGE level. RAGE knockout (RAGE−/−) and wild-type mice were subjected to chronic alcoholic feeding for 6 weeks to induce ALD, and RAGE inhibitor, iron chelator or lipid peroxidation inhibitor were administered. We showed that chronic alcohol administration triggered hepatic steatosis, inflammation, and oxidative stress, which were eliminated by deficiency or inhibition of RAGE. Surprisingly, pathways of hepatic iron metabolism were significantly altered, including increased iron uptake (Tf/TfR) and storage (Ferritin), as well as decreased iron export (FPN1/Hepcidin). In vitro experiments confirmed that RAGE had different effects on the mechanism of iron metabolism of hepatocytes and macrophages respectively. In conclusion, our data revealed preclinical evidence for RAGE inhibition as an effective intervention for alleviating alcohol-induced liver injury. [Display omitted] •The level of serum RAGE in ALD patients is related to the iron content.•RAGE mediates iron transport and storage related proteins to aggravates cellular iron deposition.•Iron metabolism in ALD involves crosstalk between hepatocytes and macrophages.•RAGE accelerates iron-dependent lipid peroxidation and inflammation in ALD.