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Role of sirtuin1 as a regulator of the gut-liver axis. Implications in health and disease

Reference	BBS/E/F/00044509
Principal Investigator / Supervisor	Dr Naiara Beraza
Co-Investigators / Co-Supervisors
Institution	Quadram Institute Bioscience
Department	Quadram Institute Bioscience Department
Funding type	Research
Value (£)	621,295
Status	Current
Type	Institute Project
Start date	01/01/2015
End date	31/03/2018
Duration	38 months

Abstract

Our aim is to investigate the role of Sirtuin1 (SIRT1), a histone deacetylase, in mediating the gut-liver axis communication to preserve health. We initially focused on defining the role of SIRT1 in the context of disturbances in bile acid metabolism. By using experimental models, we have defined that the accumulation of bile acids in the liver (during cholestasis) up-regulates SIRT1 expression, which has a detrimental impact on liver physiology. Further work aiming to define the mechanisms underlying these damaging effects has shown that SIRT1 overexpression in transgenic mice leads to inhibition of NF-kB, the main factor regulating the anti-apoptotic cell machinery. SIRT1 overexpression also alters bile acid metabolism in the liver by inhibiting FXR, further contributing to the accumulation of toxic bile acids that mediate tissue damage. Importantly, we have described that SIRT1 is highly expressed in patients with cholestatic disease, supporting the translational relevance of our findings. This part of our work is described in an article that has been submitted for publication. The regulation of bile acid metabolism is not restricted to the liver but also involves several processes in the gut. We next aimed to dissect the organ-specific function of SIRT1 in regulating bile acid metabolism and tissue homeostasis in the liver and the gut. We have produced preliminary data in intestinal-specific SIRT1 KO (SIRT1int-/-) mice showing attenuated liver injury in the context of chemically-induced intrahepatic cholestasis. We found that SIRT1int-/- mice have lower incidence of cell death in the liver that was associated with attenuated intestinal inflammation. Our future work will focus on defining the mechanism mediating the benefits of intestinal SIRT1 depletion in preserving gut function. Overall, our results pave the way to further explore the potential benefits of organ-specific modulation of SIRT1 to preserve the gut-liver axis homeostasis.

Summary

unavailable

Committee	Not funded via Committee
Research Topics	Immunology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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