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Hepatic Regulator of G Protein Signaling 6 (RGS6) drives non-alcoholic fatty liver disease by promoting oxidative stress and ATM-dependent cell death
Redox Biology ( IF 11.4 ) Pub Date : 2021-08-28 , DOI: 10.1016/j.redox.2021.102105
Tarun Mahata 1 , Abhishek Singh Sengar 1 , Madhuri Basak 1 , Kiran Das 1 , Arnab Pramanick 1 , Sumit Kumar Verma 1 , Praveen Kumar Singh 2 , Sayan Biswas 3 , Subhasish Sarkar 4 , Sudipta Saha 5 , Suvro Chatterjee 6 , Madhusudan Das 7 , Adele Stewart 8 , Biswanath Maity 1
Affiliation  

The pathophysiological mechanism(s) driving non-alcoholic fatty liver disease, the most prevalent chronic liver disease globally, have yet to be fully elucidated. Here, we identify regulator of G protein signaling 6 (RGS6), up-regulated in the livers of NAFLD patients, as a critical mediator of hepatic steatosis, fibrosis, inflammation, and cell death. Human patients with high hepatic RGS6 expression exhibited a corresponding high inflammatory burden, pronounced insulin resistance, and poor liver function. In mice, liver-specific RGS6 knockdown largely ameliorated high fat diet (HFD)-driven oxidative stress, fibrotic remodeling, inflammation, lipid deposition and cell death. RGS6 depletion allowed for maintenance of mitochondrial integrity restoring redox balance, improving fatty acid oxidation, and preventing loss of insulin receptor sensitivity in hepatocytes. RGS6 is both induced by ROS and increases ROS generation acting as a key amplification node to exacerbate oxidative stress. In liver, RGS6 forms a direct complex with ATM kinase supported by key aspartate residues in the RGS domain and is both necessary and sufficient to drive hyperlipidemia-dependent ATM phosphorylation. pATM and markers of DNA damage (γH2AX) were also elevated in livers from NAFLD patients particularly in samples with high RGS6 protein content. Unsurprisingly, RGS6 knockdown prevented ATM phosphorylation in livers from HFD-fed mice. Further, RGS6 mutants lacking the capacity for ATM binding fail to facilitate palmitic acid-dependent hepatocyte apoptosis underscoring the importance of the RGS6-ATM complex in hyperlipidemia-dependent cell death. Inhibition of RGS6, then, may provide a viable means to prevent or reverse liver damage by mitigating oxidative liver damage.



中文翻译:

G 蛋白信号转导 6 (RGS6) 的肝调节因子通过促进氧化应激和 ATM 依赖性细胞死亡来驱动非酒精性脂肪肝

导致非酒精性脂肪性肝病(全球最普遍的慢性肝病)的病理生理机制尚未完全阐明。在这里,我们确定了 G 蛋白信号传导 6 (RGS6) 的调节剂,在 NAFLD 患者的肝脏中上调,是肝脂肪变性、纤维化、炎症和细胞死亡的关键介质。具有高肝脏 RGS6 表达的人类患者表现出相应的高炎症负荷、明显的胰岛素抵抗和较差的肝功能。在小鼠中,肝脏特异性 RGS6 敲低在很大程度上改善了高脂肪饮食 (HFD) 驱动的氧化应激、纤维化重塑、炎症、脂质沉积和细胞死亡。RGS6 消耗允许维持线粒体完整性,恢复氧化还原平衡,改善脂肪酸氧化,并防止肝细胞中胰岛素受体敏感性的丧失。RGS6 既由 ROS 诱导,又增加 ROS 的产生,作为加剧氧化应激的关键放大节点。在肝脏中,RGS6 与 ATM 激酶形成直接复合物,由 RGS 结构域中的关键天冬氨酸残基支持,并且是驱动高脂血症依赖性 ATM 磷酸化的必要条件。pATM 和 DNA 损伤标志物 (γH2AX) 在 NAFLD 患者的肝脏中也升高,尤其是在 RGS6 蛋白含量高的样本中。不出所料,RGS6 敲低阻止了 HFD 喂养小鼠肝脏中的 ATM 磷酸化。此外,缺乏 ATM 结合能力的 RGS6 突变体无法促进棕榈酸依赖性肝细胞凋亡,这强调了 RGS6-ATM 复合物在高脂血症依赖性细胞死亡中的重要性。

更新日期:2021-09-14
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