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Loss of RAGE prevents chronic intermittent hypoxia-induced nonalcoholic fatty liver disease via blockade of NF-кB pathway

Abstract

In recent years, receptor for advanced glycation end-products (RAGE) has been documented to induce liver fibrosis and inflammatory reaction. Further, microarray data analysis of this study predicted high expression of RAGE in non-alcoholic fatty liver disease (NAFLD). However, its specific mechanisms remain to be elucidated. Hence, this study is aimed at investigating the mechanistic insights of RAGE in chronic intermittent hypoxia (CIH)-induced NAFLD. ApoE knockout (ApoE−/−) mice were exposed to CIH to induce NAFLD, and primary hepatocytes were also exposed to CIH to mimic in vitro setting. Accordingly, we found that RAGE and NF-κB were upregulated in the liver tissues of CIH-induced NAFLD mice and CIH-exposed hepatocytes. Depleted RAGE attenuated CIH-induced hepatocyte injury, lipid deposition, and inflammation. The relationship between RAGE and NF-κB was analyzed by in silico analysis and correlation analysis. It was demonstrated that knockdown of RAGE inhibited the NF-кB pathway, thus alleviating CIH-induced disorders in hepatocytes. Moreover, in vivo experiments also verified that depletion of RAGE alleviated CIH-induced NAFLD by inhibiting NF-кB pathway. Collectively, loss of RAGE blocked the NF-кB pathway to alleviate CIH-induced NAFLD, therefore, highlighting a potential hepatoprotective target for treating NAFLD.

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Fig. 1: RAGE expression is elevated in CIH-induced NAFLD ApoE−/− mice.
Fig. 2: RAGE knockdown restrains CIH-induced hepatocyte injury and lipid deposition.
Fig. 3: Downregulation of RAGE blockades the NF-кB pathway.
Fig. 4: Downregulation of RAGE relieves lipid deposition in the CIH-induced hepatocytes via inhibiting NF-кB pathway.
Fig. 5: Knockout of RAGE alleviates NAFLD induced by CIH via inhibiting NF-кB pathway in vivo.
Fig. 6: Schematic representation of molecular mechanism of RAGE in CIH-induced NAFLD.

Data availability

All data generated or analyzed during this study are included in this article (and/or) its supplemental material file. Further enquiries can be directed to the corresponding author.

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Acknowledgements

This study was supported by Key Project of Jiangxi Provincial Education Department (No. GJJ190026), the National Natural Science Foundation of China (No. 82060025), and the Natural Science Foundation of Jiangxi Province (No. 2019BAB205002).

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HT: Conceptualization, Data Curation, Formal analysis, Writing—Original Draft, Writing—Review & Editing; JH: Conceptualization, Investigation, Methodology, Writing—Review & Editing; WZ: Resources, Supervision, Writing—Original Draft; YH: Software, Writing—Original Draft; JC: Visualization, Writing—Original Draft; FG: Validation, Writing—Original Draft; WB: Conceptualization, Project administration, Writing—Review & Editing

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Correspondence to Wei Bai.

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Tan, H., Hu, J., Zuo, W. et al. Loss of RAGE prevents chronic intermittent hypoxia-induced nonalcoholic fatty liver disease via blockade of NF-кB pathway. Gene Ther (2022). https://doi.org/10.1038/s41434-022-00351-4

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