Characterising the role of SIRT1 in macrophage function during bile acid metabolism disturbances

Isaacs, Anna (2021) Characterising the role of SIRT1 in macrophage function during bile acid metabolism disturbances. Doctoral thesis, University of East Anglia.

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Abstract

Inflammation is the hallmark of cholestasis. Macrophages promote the inflammatory response however their precise role or how metabolism may control their function during cholestasis is enigmatic. Silent information regulator type 1 (SIRT1) is a master metabolic regulator and metabolism underpins macrophage activation, thus we here aim to characterise its role in macrophage activation during cholestasis. Also, while cholestasis associates with changes in the intestinal microbiome composition, its impact in the pathogenesis of the disease is undefined.

Here, we used conventionalised germ free animals and induced cholestasis with α-naphthylisothiocyanate. Also, we used endotoxin to induce liver inflammation in wild type and SIRT1 overexpressing animals. We performed transfer of WT and SIRT1 overexpressing myeloid cells and induced cholestasis by bile duct ligation (BDL). Lastly, we subjected myeloid-cell specific SIRT1 knockout mice to BDL.

We demonstrated that the microbiome synergises with bile acids to promote liver damage and macrophage recruitment during cholestasis.

Also, we identified that SIRT1 overexpression promotes liver inflammation in response to endotoxin that associated with increased inflammasome activation in vivo. Mechanistically, macrophage SIRT1 overexpression associated with the activation of the mTOR pathway and metabolic rewiring, as well as increased inflammasome activation and delayed autophagy after endotoxin.

During cholestasis, the overexpression of SIRT1 associated with increased inflammation and the transfer of myeloid SIRT1 overexpressing cells led to increased liver injury and fibrosis, indicating that myeloid SIRT1 contributes to the progression of cholestasis.

Our results suggested that myeloid SIRT1 could be a therapeutic target during cholestasis, therefore we investigated myeloid SIRT1 depletion in response to BDL. Interestingly, we discovered that myeloid SIRT1 depletion contributed to the pathogenesis of cholestasis.

Overall, we identify the role for SIRT1 in macrophage activation during inflammatory liver disease. Our findings point to the modulation, but not complete ablation, of SIRT1 in myeloid cells to preserve liver health.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Biological Sciences
Depositing User:	Chris White
Date Deposited:	16 Mar 2022 14:50
Last Modified:	16 Mar 2022 14:50
URI:	https://ueaeprints.uea.ac.uk/id/eprint/84080
DOI:

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