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Farnesoid X receptor (FXR) inhibits coagulation process via inducing hepatic antithrombin III expression in mice

LUAN Zhi-Lin^1,2, WEI Yuan-Yi^1,2, WANG Yuan-Chen¹, MING Wen-Hua¹, ZHANG Hai-Bo¹, WANG Bing^1,3, CUI Xiao-Hui^1,3, LI Yu-Yuan^1,2, GUAN You-Fei^1,2, ZHANG Xiao-Yan^4,*

¹Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China；²Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China；³Department of Endocrinology, Dalian Municipal Central Hospital, Dalian Medical University, Dalian 116033, China ；⁴Health Science Center, East China Normal University, Shanghai 200241, China

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.

Key words: farnesoid X receptor (FXR); antithrombin III (AT III); anticoagulation; GW4064

Received: 2021-06-29　　Accepted: 2021-07-14

Corresponding author: 张晓燕　　E-mail: wserien@163.com

DOI: 10.13294/j.aps.2021.0075

Citing This Article：

LUAN Zhi-Lin, WEI Yuan-Yi, WANG Yuan-Chen, MING Wen-Hua, ZHANG Hai-Bo, WANG Bing, CUI Xiao-Hui, LI Yu-Yuan, GUAN You-Fei, ZHANG Xiao-Yan. Farnesoid X receptor (FXR) inhibits coagulation process via inducing hepatic antithrombin III expression in mice. Acta Physiol Sin 2021; 73 (5): 795-804