Metabolic Regulation of Macrophages by SIRT1 Determines Activation During Cholestatic Liver Disease in Mice.
Metabolic Regulation of Macrophages by SIRT1 Determines Activation During Cholestatic Liver Disease in Mice.
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DOI：
10.1016/j.jcmgh.2021.12.010
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发表时间：
2022
影响因子：
7.2
通讯作者：
Beraza N
中科院分区：
文献类型：
--
作者：
Isaacs-Ten A;Moreno-Gonzalez M;Bone C;Martens A;Bernuzzi F;Ludwig T;Hellmich C;Hiller K;Rushworth SA;Beraza N
炎症是慢性肝病的标志。代谢是调节免疫细胞激活的关键决定因素。在这里，我们定义了沉默调节蛋白 1 (SIRT1)（一种主要的代谢调节因子）在控制胆汁淤积性肝病期间巨噬细胞的激活以及响应内毒素方面的作用。我们使用了过度表达 SIRT1 的小鼠，并通过腹腔内脂多糖进行治疗或通过胆管结扎诱导胆汁淤积。骨髓来源的巨噬细胞用于体外机制研究。最后，PEPC-Boy 小鼠被用于过继转移实验，以阐明 SIRT1 过表达巨噬细胞对胆汁淤积性肝病的影响。我们发现SIRT1过表达会促进脂多糖/GalN和胆管结扎后肝脏炎症和肝损伤的增加；这与巨噬细胞中炎症小体的激活增加有关。从机制上讲，SIRT1 过表达与哺乳动物雷帕霉素靶点 (mTOR) 通路的激活相关，从而导致巨噬细胞的激活增加，这表明在体外对内毒素的反应导致代谢重新布线，糖酵解增加和三羧酸循环破坏。巨噬细胞中 SIRT1/mTOR 轴的激活与炎症小体的激活和自噬的减弱相关。最终，在胆汁淤积性疾病的体内模型中，SIRT1 过度表达的骨髓细胞的移植导致了肝损伤和纤维化。我们的研究为胆汁淤积性疾病期间巨噬细胞的调节以及对内毒素的反应提供了新的机制见解，其中 SIRT1/mTOR 串扰调节巨噬细胞活化，控制炎症小体、自噬和代谢重连。
Inflammation is the hallmark of chronic liver disease. Metabolism is a key determinant to regulate the activation of immune cells. Here, we define the role of sirtuin 1 (SIRT1), a main metabolic regulator, in controlling the activation of macrophages during cholestatic liver disease and in response to endotoxin. We have used mice overexpressing SIRT1, which we treated with intraperitoneal lipopolysaccharides or induced cholestasis by bile duct ligation. Bone marrow–derived macrophages were used for mechanistic in vitro studies. Finally, PEPC-Boy mice were used for adoptive transfer experiments to elucidate the impact of SIRT1-overexpressing macrophages in contributing to cholestatic liver disease. We found that SIRT1 overexpression promotes increased liver inflammation and liver injury after lipopolysaccharide/GalN and bile duct ligation; this was associated with an increased activation of the inflammasome in macrophages. Mechanistically, SIRT1 overexpression associated with the activation of the mammalian target of rapamycin (mTOR) pathway that led to increased activation of macrophages, which showed metabolic rewiring with increased glycolysis and broken tricarboxylic acid cycle in response to endotoxin in vitro. Activation of the SIRT1/mTOR axis in macrophages associated with the activation of the inflammasome and the attenuation of autophagy. Ultimately, in an in vivo model of cholestatic disease, the transplantation of SIRT1-overexpressing myeloid cells contributed to liver injury and fibrosis. Our study provides novel mechanistic insights into the regulation of macrophages during cholestatic disease and the response to endotoxin, in which the SIRT1/mTOR crosstalk regulates macrophage activation controlling the inflammasome, autophagy and metabolic rewiring.
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Sirtuins是否可行的目标可以改善健康状态和寿命？
DOI：
10.1038/nrd3738
发表时间：
2012-06-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Baur JA;Ungvari Z;Minor RK;Le Couteur DG;de Cabo R
通讯作者：
de Cabo R
DOI：
10.1038/labinvest.2014.151
发表时间：
2015-02
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
--
作者：
通讯作者：
--
影响因子：
16
作者：
Duran A;Amanchy R;Linares JF;Joshi J;Abu-Baker S;Porollo A;Hansen M;Moscat J;Diaz-Meco MT
通讯作者：
Diaz-Meco MT
影响因子：
13.5
作者：
Garcia-Rodriguez, Juan L.;Barbier-Torres, Lucia;Fernandez-Alvarez, Sara;Gutierrez-de Juan, Virginia;Monte, Maria J.;Halilbasic, Emina;Herranz, Daniel;Alvarez, Luis;Aspichueta, Patricia;Marin, Jose J. G.;Trauner, Michael;Mato, Jose M.;Serrano, Manuel;Beraza, Naiara;Luz Martinez-Chantar, Maria
通讯作者：
Luz Martinez-Chantar, Maria
影响因子：
7.4
作者：
Hiller, Karsten;Hangebrauk, Jasper;Schomburg, Dietmar
通讯作者：
Schomburg, Dietmar