Fine-tuning of SIRT1 expression is essential to protect the liver from cholestatic liver disease.

Blokker B. A., Maijo M., Echeandia M., Galduroz M., Patterson A. M., Ten A., Philo M., Schungel R., Gutierrez-de Juan V., Halilbasic E., Fuchs C., Le Gall G., Milkiewicz M., Milkiewicz P., Banales J. M., Rushbrook S. M., Mato J. M., Trauner M., Müller M., Martínez-Chantar M. L., Varela-Rey M., Beraza N.. (2018)

Hepatology (Baltimore, Md.)

Cholestasis comprises aetiologically heterogeneous conditions characterized by accumulation of bile acids in the liver that actively contribute to liver damage. Sirtuin 1 (SIRT1) regulates liver regeneration and bile acid metabolism via modulating the farnesoid X receptor (FXR); we here investigate its role in cholestatic liver disease. We determined SIRT1 expression in livers from patients with cholestatic disease, in two experimental models of cholestasis, as well as in human and murine liver cells in response to bile acid loading. SIRT1 overexpressing (SIRToe ) and hepatocyte-specific SIRT1-KO mice (SIRThep-/- ) were subjected to BDL and were fed with 0.1%DDC diet to determine the biological relevance of SIRT1 during cholestasis. The effect of NorUDCA was tested in BDL/SIRToe mice. We found that SIRT1 was highly expressed in livers from cholestatic patients, mice after BDL and Mdr2-/- animals. The detrimental effects of SIRT1 during cholestasis were validated in vivo and in vitro. SIRToe mice showed exacerbated parenchymal injury whereas SIRThep-/- mice evidenced a moderate improvement after BDL and 0.1%DDC feeding. Likewise, hepatocytes isolated from SIRToe mice showed increased apoptosis in response to bile acids, while a significant reduction was observed in SIRThep-/- hepatocytes. Importantly, the decrease, but not complete inhibition of SIRT1 exerted by NorUDCA treatment correlated with pronounced improvement in liver parenchyma in BDL/SIRToe mice. Interestingly, both SIRT1 overexpression and hepatocyte-specific SIRT1 depletion correlated with inhibition of the farnesoid X receptor (FXR), whereas modulation of SIRT1 by NorUDCA associated with restored FXR-signalling.

Hepatology (Baltimore, Md.)

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