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.

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