Efficacy and mechanism of inhibition of the GPR30-PI3K pathway by 4-phenylbutyric acid in the treatment of intrahepatic cholestasis of pregnancy

Abstract

Intrahepatic cholestasis of pregnancy (ICP) is a liver disease that manifests predominantly in the later stages of pregnancy. The primary treatment currently involves the use of ursodeoxycholic acid (UDCA). In this study, the therapeutic effectiveness of 4-phenylbutyric acid (4-PBA) in the treatment of ICP, as well as the potential mechanisms involved, are investigated to offer new references for clinical treatment decisions using ICP model. The therapeutic effect of 4-PBA on ICP was evaluated by drug therapy on ICP cells and animal models, and corresponding fluorescence immunoassay, electron microscope, WB and other experiments. In addition, the cells and animals treated with GPR30 inhibitor were treated to investigate whether 4-PBA promoted the expression of bile salt output pump (BSEP) protein through GPR30-PI3K pathway, thereby promoting bile acid excretion. Administration of 4-PBA significantly reduced the incidence of stillbirth associated with ICP. 4-PBA was effective in decreasing serum bile acid levels, reducing the activation of the GPR30-PI3K pathway, and increasing the expression of BSEP protein in hepatocytes. 4-PBA was effective in reducing bile acid levels and significantly improving fetal outcomes associated with ICP. The potential mechanism involves the promotion of BSEP localization and expression in the hepatocytes’ microvilli structures via the GPR30-PI3K pathway.