Abstract
Non-alcoholic fatty liver disease (NAFLD) has become a growing public health problem. However, the complicated pathogenesis of NAFLD contributes to the deficiency of effective clinical treatment. Here, we demonstrated that liver-specific loss of Arid2 induced hepatic steatosis and this progression could be exacerbated by HFD. Mechanistic study revealed that ARID2 repressed JAK2-STAT5-PPARĪ³ signaling pathway by promoting the ubiquitination of JAK2, which was mediated by NEDD4L, a novel E3 ligase for JAK2. ChIP assay revealed that ARID2 recruited CARM1 to increase H3R17me2a level at the NEDD4L promoter and activated the transcription of NEDD4L. Moreover, inhibition of Jak2 by Fedratinib in liver-specific Arid2 knockout mice alleviated HFD-induced hepatic steatosis. Downregulation of ARID2 and the reverse correlation between ARID2 and JAK2 were also observed in clinical samples. Therefore, our study has revealed an important role of ARID2 in the development of NAFLD and provided a potential therapeutic strategy for NAFLD.
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Data availability
RNA-seq data supporting the results of this study have been deposited in the NCBI GEO database under accession number GSE216171. All the other data supporting the findings of this study are available within the article and itsĀ Supplementary Information files and from the corresponding author upon reasonable request.
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Acknowledgements
We thank Zhonghui Weng, Yifan Bu and Lin Qiu from Institutional Center for Shared Technologies and Facilities of SINH, CAS for technical assistance. We appreciate the New World Group for their Charitable Foundation to establish the Institute for Nutritional Sciences, SIBS, CAS-New World Joint laboratory, which have given full support to this study.
Funding
This work was supported by the National Natural Science Foundation of China (81972757 and 82172950), Youth Innovation Promotion Association of Chinese Academy of Sciences grant (2017324) and Sanofi-SIBS 2018 Young Faculty Award to Jing-Jing Li and the National Natural Science Foundation of China (82030084 and 81730083) to Dong Xie.
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HC, JL and DX conceived the project and designed the research studies. HC performed most of the experiments described. HJ, KD, XQ, NM, FZ, YW, QZ and JX provided help with animal and technical assistance in the mouse experiments. QN, SX and BZ assisted with the in vitro assays. BZ provided conceptual advice and helpful discussion. HC analyzed data. HC, JL and DX wrote the manuscript.
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Experiments about human tissues have been approved by the Biomedical Research Ethics Committee, Shanghai Institute for Biological Science, CAS in 2019 (ER-SIBS-251902). All animal studies were performed under the approval of the Institutional Animal Care and Use Committee of Shanghai Institute of Nutrition and Health, CAS (IACUC, SINH, CAS).
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Cao, HJ., Jiang, H., Ding, K. et al. ARID2 mitigates hepatic steatosis via promoting the ubiquitination of JAK2. Cell Death Differ 30, 383ā396 (2023). https://doi.org/10.1038/s41418-022-01090-0
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DOI: https://doi.org/10.1038/s41418-022-01090-0
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