Protective effects of SRT1720 via the HNF1α/FXR signalling pathway and anti-inflammatory mechanisms in mice with estrogen-induced cholestatic liver injury

Abstract

Sirtuin 1 (SIRT1) is the most conserved mammalian NAD+-dependent protein deacetylase and is a member of the silent information regulator 2 (Sir2) families of proteins (also known as Sirtuins). In the liver, hepatic SIRT1 modulates bile acid metabolism through the regulation of farnesoid X receptor (FXR) expression. FXR is one of the most important nuclear receptors involved in the regulation of bile acid metabolism. SIRT1 modulates the FXR expression at multiple levels, including direct deacetylation of this transcription factor and transcriptional regulation through hepatocyte nuclear factor 1α (HNF1α). Therefore, hepatic SIRT1 is a vital regulator of the HNF1α/FXR signalling pathway and hepatic bile acid metabolism. However, whether SIRT1 is a suitable therapeutic target for the treatment of cholestasis is unknown. In the present study, we examined the protective effect of SRT1720, which is a specific activator of SIRT1, against 17α-ethinylestradiol (EE)-induced cholestasis in mice. Our data demonstrated that SRT1720 significantly prevented EE-induced changes in the serum levels of total bile acids (TBA), total bilirubin (TBIL), γ-glutamyltranspeptidase (γ-GGT) and alkaline phosphatase (ALP). SRT1720 also relieved EE-induced liver pathological injuries as indicated by haematoxylin and eosin (H&E) staining. SRT1720 treatment protected against EE-induced liver injury through the HNF1α/FXR signalling pathway, which up-regulated the expression of hepatic efflux transporter (Bsep and Mrp2) and hepatic uptake transporters (Ntcp and Oatp1b2). Moreover, SRT1720 significantly inhibited the TNF-α and IL-6 levels induced by EE. These findings indicate that SRT1720 exerts a dose-dependent protective effect on EE-induced cholestatic liver injury in mice and that the mechanism underlying this activity is related to the activation of the HNF1α/FXR signalling pathway and anti-inflammatory mechanisms.