Tudor staphylococcal nuclease (Tudor-SN) regulates activation of quiescent hepatic stellate cells.

Baoxin Qian, Yan Zhao, Xinxin Zhang, Chunyan Zhao, Xiaoteng Cui, Fengmei Wang, Xiang Jing, Lin Ge, Zhi Yao, Xingjie Gao, Jie Yang
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Abstract

Several liver diseases have been associated with the Tudor staphylococcal nuclease (Tudor-SN) protein. Our previous results demonstrated that, in comparison to wild-type (WT) mice, systemic overexpression of Tudor-SN in transgenic (Tg) mice (Tudor-SN-Tg) ameliorates obesity-induced insulin resistance and hepatic steatosis. In this study, we observed an inverse correlation in the expression levels of Tudor-SN and profibrogenic factors, such as alpha-smooth muscle actin (α-SMA) and collagen alpha-1(I) chain (COL1A1), in liver tissue samples between Tudor-SN-Tg and WT mice. The correlation was further validated in hepatic fibrotic tissues from patients with cirrhosis and fibrosis. Utilizing a carbon tetrachloride (CCl4)-induced hepatic fibrosis model, we observed that Tudor-SN attenuated hepatic fibrosis in mice. Tudor-SN was abundantly expressed in hepatic stellate cells (HSCs). In the Tudor-SN-Tg group, primary HSCs showed stellate-like morphology as well as reduced in vitro proliferation and chemotactic ability compared to the WT group. Pseudotime series analysis of HSCs further showed the role of Tudor-SN during the dynamic evolution of HSC activation. Reduced Tudor-SN expression facilitated the in vitro activation of LX-2 cells. Furthermore, primary HSC cells from WT and Tudor-SN knockout (KO) mice were isolated for RNA-sequencing analysis. The findings suggested that Tudor-SN may regulate the activation of primary HSCs by influencing lipid metabolism, translation initiation, immune response, and the extracellular matrix. In summary, we identified Tudor-SN as a newly identified regulator involved in the transition of quiescent HSCs to activated states, shedding light on the antifibrotic impact of Tudor-SN expression in the development of hepatic fibrosis.

Tudor葡萄球菌核酸酶(Tudor- sn)调节静止的肝星状细胞的激活。
几种肝脏疾病与都铎葡萄球菌核酸酶(Tudor- sn)蛋白有关。我们之前的研究结果表明,与野生型(WT)小鼠相比,转基因(Tg)小鼠(Tudor-SN-Tg)的系统过表达Tudor-SN可改善肥胖诱导的胰岛素抵抗和肝脏脂肪变性。在本研究中,我们观察到Tudor-SN- tg与WT小鼠肝组织样本中α-平滑肌肌动蛋白(α-SMA)和胶原α- 1(I)链(COL1A1)等促纤维化因子的表达水平呈负相关。在肝硬化和纤维化患者的肝纤维化组织中进一步证实了这种相关性。利用四氯化碳(CCl4)诱导的肝纤维化模型,我们观察到Tudor-SN减轻了小鼠的肝纤维化。Tudor-SN在肝星状细胞(hsc)中大量表达。与WT组相比,Tudor-SN-Tg组原代造血干细胞呈现星状形态,体外增殖和趋化能力降低。对HSC的伪时间序列分析进一步显示了Tudor-SN在HSC激活的动态演化过程中的作用。Tudor-SN表达的降低促进了LX-2细胞的体外活化。此外,分离WT和Tudor-SN敲除(KO)小鼠的原代HSC细胞进行rna测序分析。结果提示Tudor-SN可能通过影响脂质代谢、翻译起始、免疫反应和细胞外基质来调节原代hsc的活化。总之,我们发现Tudor-SN是一种新发现的调节因子,参与了静止hsc向激活状态的转变,揭示了Tudor-SN表达在肝纤维化发展中的抗纤维化作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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