Metabolic regulation of macrophages by SIRT1 determines activation during cholestatic liver disease in mice

Isaacs-Ten, Anna, Moreno-Gonzalez, Mar, Bone, Caitlin, Martens, Andre, Bernuzzi, Federico, Ludwig, Tobias, Hellmich, Charlotte, Hiller, Karsten, Rushworth, Stuart A. and Beraza, Naiara (2022) Metabolic regulation of macrophages by SIRT1 determines activation during cholestatic liver disease in mice. Cellular and Molecular Gastroenterology and Hepatology, 13 (4). pp. 1019-1039. ISSN 2352-345X

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Background & Aims: 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. Methods: 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. Results: 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. Conclusions: 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.

Item Type: Article
Uncontrolled Keywords: cholestasis,inflammasome,macrophages,metabolism,sirt1,hepatology,gastroenterology ,/dk/atira/pure/subjectarea/asjc/2700/2721
Faculty \ School: Faculty of Science > School of Biological Sciences
Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 05 Jan 2022 13:30
Last Modified: 22 Oct 2022 16:34
DOI: 10.1016/j.jcmgh.2021.12.010

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