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

Anna Isaacs-Ten, Mar Moreno-Gonzalez, Caitlin Bone, Andre Martens, Federico Bernuzzi, Tobias Ludwig, Charlotte Hellmich, Karsten Hiller, Stuart A. Rushworth, Naiara Beraza

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Abstract

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.

Original languageEnglish
Pages (from-to)1019-1039
Number of pages21
JournalCellular and Molecular Gastroenterology and Hepatology
Volume13
Issue number4
Early online date22 Dec 2021
DOIs
Publication statusPublished - 1 Jan 2022

Keywords

  • Cholestasis
  • Inflammasome
  • Macrophages
  • Metabolism
  • SIRT1

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