The role of intestinal SIRT1 in liver regeneration

Seaman, Sian Georgia (2023) The role of intestinal SIRT1 in liver regeneration. Doctoral thesis, University of East Anglia.

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Sirtuin 1 (SIRT1) is recognised as an important regulator of bile acid (BA) metabolism in the liver and intestine. In the liver, SIRT1 has previously been hailed as crucial for successful liver regeneration by regulating BA homeostasis via FXR. However, despite these findings and the recent interest in the gut-liver axis, the role of intestinal SIRT1 in liver regeneration remains undefined.

The aim of this research was to define the role of intestinal SIRT1 in liver regeneration. We performed partial hepatectomy (PHx) on intestinal-specific SIRT1 knockout mice (SIRT1intKO) to stimulate liver regeneration. Liver and intestinal tissues were analysed utilising qPCR, immunoblotting, immunohistochemistry, and liquid chromatography-mass spectrometry to determine the impact of intestinal SIRT1 deletion on histology, bile acid metabolism and hepatocyte proliferation during liver regeneration.

Our results demonstrate that in the absence of intestinal SIRT1, expression of intestinal bile acid metabolism factors, FXR and FGF15 was dysregulated, which led to disrupted bile acid homeostasis and profuse liver injury, suggesting increased hepatocyte death due to BA toxicity. Additionally, SIRT1intKO mice displayed impaired hepatocyte proliferation compared to WT which correlated with increased abundance of senescent hepatocytes shown by immunohistochemical analysis of P21. Remarkably, at 10d post-PHx, SIRT1intKO mice obtained a liver weight: body weight ratio comparable to WT pointing to complete regeneration. Further investigation into an alternative means of regeneration revealed that SIRT1intKO mice had increased presence of liver progenitor cells as indicated by immunohistochemistry for cytokeratin-19 (CK-19), denoting activation of the liver stem cell compartment to reconstitute the liver mass.

Overall, we define intestinal SIRT1 as a crucial regulator of liver regeneration through its ability to maintain BA homeostasis and promote hepatocyte proliferation. Our research points towards the FXR-FGF15-FGFR4 axis as the mechanistic mediator of the effects of intestinal SIRT1 and highlights the importance of the gut-liver axis during liver regeneration.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Nicola Veasy
Date Deposited: 29 Jan 2024 09:22
Last Modified: 29 Jan 2024 09:22


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