Activation of the farnesoid X receptor represses PCSK9 expression in human hepatocytes

Abstract 

The purpose of this study was to determine whether bile acids (BAs) modulate hepatic pro-protein convertase subtilisin/kexin 9 (PCSK9) gene expression. Immortalized human hepatocytes were treated with various BAs. Chenodeoxycholic acid (CDCA) treatment specifically decreased both PCSK9 mRNA and protein contents. Moreover, activation of the BA-activated farnesoid X receptor (FXR) by its synthetic specific agonist GW4064 also decreased PCSK9 expression. Of functional relevance, coadministration of CDCA counteracted the statin-induced PCSK9 expression, leading to a potentiation of LDL receptor activity. This study suggests that a transcriptional repression of PCSK9 by CDCA or FXR agonists may potentiate the hypolipidemic effect of statins.

Abbreviations: BA, bile acid, CA, cholic acid, CDCA, chenodeoxycholic acid, DCA, deoxycholic acid, FXR, farnesoid X receptor, IHH, immortalized human hepatocytes, LA, lithocholic acid, LDL-c, low density lipoprotein cholesterol, LDLr, low density lipoprotein receptor, PCSK9, pro-protein convertase subtilisin/kexin 9, PXR, pregnane X receptor, UDCA, ursodeoxycholic acid

Keywords: PCSK9, Bile acid, FXR, Statin, LDL-cholesterol