Targeting FXR in hepatocytes: a promising approach to enhance fibrinolysis and reduce deep vein thrombosis risk

ABSTRACT: Obesity is a major health issue and a risk factor for venous thromboembolic disease. Plasminogen activator inhibitor 1 (PAI-1), encoded by the gene SERPINE1, is a negative regulator of fibrinolysis and has been associated with obesity. The liver, which senses obesity-induced metabolic stress, is a key determinant of circulating PAI-1 levels. However, the mechanisms underlying the increased PAI-1 expression in obesity are unclear. This study investigated the upstream regulation of PAI-1 and its role in fibrinolysis and deep vein thrombosis (DVT). Compared with lean mice, diet-induced obesity mice presented significantly shorter fibrinolysis times and larger venous thrombi, largely due to increased hepatocyte expression of PAI-1. A publicly available single-cell RNA sequence data set from the livers of individuals with obesity suggested that increased PAI-1 expression may be related to reduced hepatocyte farnesoid X receptor (FXR) signaling. FXR activation also suppressed Serpine1 mRNA and PAI-1 protein expression levels in both mice and primary mouse hepatocytes (MPHs), but a decrease in PAI-1 in MPHs of Fxr-null mice after FXR activation was not observed. Both Fxr-null mice and Fxrfl/fl mice with AAV8-TBG-Cre exhibited significantly elevated plasma PAI-1, resulting in further impaired fibrinolysis and increased DVT burden. Dual-luciferase reporter assays and chromatin immunoprecipitation suggested that FXR activation directly represses Serpine1 transcription. Importantly, tropifexor treatment of obese mice lowered plasma PAI-1 levels and further alleviated fibrinolysis and the DVT load. These findings suggest that targeting FXR in hepatocytes may improve fibrinolysis and reduce DVT risk.