ARID2 mitigates hepatic steatosis via promoting the ubiquitination of JAK2
ARID2 mitigates hepatic steatosis via promoting the ubiquitination of JAK2
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DOI：
10.1038/s41418-022-01090-0
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发表时间：
2022-11-17
影响因子：
12.4
通讯作者：
Li, Jing-Jing
中科院分区：
文献类型：
--
作者：
Cao, Hui-Jun;Jiang, Hao;Li, Jing-Jing
非酒精性脂肪性肝病（NAFLD）已成为日益严重的公共卫生问题。然而，NAFLD的发病机制复杂，临床上缺乏有效的治疗方法。在这里，我们证明了肝脏特异性Arid 2的丢失诱导了肝脏脂肪变性，并且这种进展可能会因HFD而加剧。机制研究表明，ARID 2通过促进JAK 2的泛素化抑制JAK 2-STAT 5-PPAR γ信号通路，这种泛素化是由一种新的JAK 2的E3连接酶NEDD 4L介导的。ChIP分析显示，ARID 2募集CARM 1以增加NEDD 4L启动子处的H3 R17 me 2a水平，并激活NEDD 4L的转录。此外，在肝脏特异性Arid 2敲除小鼠中，Fedratinib对Jak 2的抑制减轻了HFD诱导的肝脂肪变性。在临床样本中也观察到ARID 2的下调以及ARID 2和JAK 2之间的反向相关性。因此，我们的研究揭示了ARID 2在NAFLD发展中的重要作用，并为NAFLD提供了潜在的治疗策略。
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-PPAR gamma 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.