SIRT7 Promotes Alcohol Associated Liver Injury via Modulating Myeloid Cell CCL2 Secretion through NF-κB Signaling Pathway.

IF 4.7 2区 医学 Q1 PATHOLOGY
Zhiqiang Wang, Gaoshuang Liang, Jinying Peng, Yiying Gu, Xiangwen Zhang, Cong Ding, Tingzi Yu, Zhuan Li
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引用次数: 0

Abstract

The pathogenesis of Alcohol-associated liver disease (ALD) is complex, involving ethanol-induced enhancement of gut permeability results in the release of bacterial products from the intestine. This triggers intrahepatic inflammation and liver damage, with hepatic macrophages playing key roles in the inflammatory response to alcohol. SIRT7 a NAD+-dependent type III histone deacetylase, is being recognized as a potential therapeutic target in various human diseases including cancer. Emerging evidence show that SIRT7 participates in immune regulation whether is involve in ALD remain elusive. In present study using myeloid cell-specific Sirt7 knockout mice (Lyz2-Sirt7-/-), we observed that knockout Sirt7 in myeloid cells significantly ameliorated alcohol-induced liver injury, inflammation, and cell infiltration, while only mildly affecting lipid metabolism pathways. We further identified CCL2 as the main target impaired by Sirt7 knockout after alcohol. In vitro studies confirmed that Sirt7 knockout impaired macrophages' ability of CCL2 secretion and monocyte recruiting, and exogenous CCL2 reversed this impairment. At molecular level, we found that knockout of Sirt7 significantly impaired LPS induced p65 phosphorylation and nuclear localization. More importantly, the SIRT7 inhibitor 40569 sufficiently decreased alcohol induced liver injury and hepatic inflammation via preventing CCL2 in vivo. Our data thus uncover previously undescribed role of myeloid SIRT7 in mediating ALD via promoting CCL2 secretion through NF-κB signaling pathway. Targeting SIRT7 might offer novel mechanism based therapeutic options of ALD.

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来源期刊
CiteScore
11.40
自引率
0.00%
发文量
178
审稿时长
30 days
期刊介绍: The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.
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