Protective effects of SRT1720 via the HNF1α/FXR signalling pathway and anti-inflammatory mechanisms in mice with estrogen-induced cholestatic liver injury.
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.
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, Nanjing 210009, China.
Linxi
L
Yu
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, Nanjing 210009, China.
Xiaoxin
X
Liu
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, Nanjing 210009, China.
Xiaojiaoyang
X
Li
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, Nanjing 210009, China.
Zihang
Z
Yuan
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, Nanjing 210009, China.
Hang
H
Yang
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: lyzhang@cpu.edu.cn.
Luyong
L
Zhang
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, Nanjing 210009, China. Electronic address: beaglejiang@cpu.edu.cn.
Zhenzhou
Z
Jiang
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001647:Bile Acids and Salts / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy*; D002779:Cholestasis / Q000139:chemically induced / Q000188:drug therapy*; D004997:Ethinyl Estradiol / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000096:biosynthesis* / Q000235:genetics; D006576:Heterocyclic Compounds, 4 or More Rings / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D061251:Primary Cell Culture; D020011:Protective Agents / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D000099150:Receptor, Farnesoid X-Activated
D000893:Anti-Inflammatory Agents; D001647:Bile Acids and Salts; D004997:Ethinyl Estradiol; D051538:Hepatocyte Nuclear Factor 1-alpha; D006576:Heterocyclic Compounds, 4 or More Rings; D020011:Protective Agents; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C525422:SRT1720
Bsep; Cholestasis; EE; FXR; HNF1α; IL-6; Mrp2; SRT1720; TNF-α