Farnesoid X receptor (FXR) inhibits coagulation process via inducing hepatic antithrombin III expression in mice.
- Author:
Zhi-Lin LUAN
1
;
Yuan-Yi WEI
1
;
Yuan-Chen WANG
1
;
Wen-Hua MING
1
;
Hai-Bo ZHANG
1
;
Bing WANG
1
;
Xiao-Hui CUI
1
;
Yu-Yuan LI
1
;
You-Fei GUAN
1
;
Xiao-Yan ZHANG
2
Author Information
1. Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China.
2. Health Science Center, East China Normal University, Shanghai 200241, China. wserien@163.com.
- Publication Type:Journal Article
- MeSH:
Animals;
Antithrombin III;
Blood Coagulation;
Hepatocytes;
Liver;
Mice;
Mice, Inbred C57BL;
Mice, Knockout;
Receptors, Cytoplasmic and Nuclear/genetics*
- From:
Acta Physiologica Sinica
2021;73(5):795-804
- CountryChina
- Language:English
-
Abstract:
Farnesoid X receptor (FXR) has been identified as an inhibitor of platelet function and an inducer of fibrinogen protein complex. However, the regulatory mechanism of FXR in hemostatic system remains incompletely understood. In this study, we aimed to investigate the functions of FXR in regulating antithrombin III (AT III). C57BL/6 mice and FXR knockout (FXR KO) mice were treated with or without GW4064 (30 mg/kg per day). FXR activation significantly prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT), lowered activity of activated factor X (FXa) and concentrations of thrombin-antithrombin complex (TAT) and activated factor II (FIIa), and increased level of AT III, whereas all of these effects were markedly reversed in FXR KO mice. In vivo, hepatic AT III mRNA and protein expression levels were up-regulated in wild-type mice after FXR activation, but down-regulated in FXR KO mice. In vitro study showed that FXR activation induced, while FXR knockdown inhibited, AT III expression in mouse primary hepatocytes. The luciferase assay and ChIP assay revealed that FXR can bind to the promoter region of AT III gene where FXR activation increased AT III transcription. These results suggest FXR activation inhibits coagulation process via inducing hepatic AT III expression in mice. The present study reveals a new role of FXR in hemostatic homeostasis and indicates that FXR might act as a potential therapeutic target for diseases related to hypercoagulation.
