A grape seed procyanidin extract lowers serum triglyceride levels via selective modulation of intestinal FXR‐target gene expression and inhibition of enterohepatic bile acid recirculation (1045.35)

Abstract

As ligands of the farnesoid x receptor (FXR), bile acids (BA) play an essential role in maintaining triglyceride (TG) homeostasis. We previously showed that a grape seed procyanidin extract (GSPE) decreases serum TG levels via repression of sterol regulatory element binding protein 1c (SREBP1c) in a FXR‐dependent manner. We now propose an additional novel mechanism by which GSPE lowers TG levels, wherein GSPE selectively modulates intestinal FXR‐target gene expression, therefore altering enterohepatic BA recirculation. Studies were performed using human colorectal adenocarcinoma cells (Caco2) and wild type (WT) and FXR‐/‐ mice. Results, from both in vitro and in vivo studies, show that GSPE represses the expression of the apical sodium‐dependent bile acid transporter (ASBT), while also inhibiting the expression of intestinal bile acid‐binding protein (IBABP), thereby impacting BA uptake and transport through the enterocyte. Concomitantly, a 43% decrease in serum BA levels was observed in vivo following GSPE administration in WT mice. Hepatic CYP7A1, the gene encoding cholesterol 7α‐hydroxylase, the rate‐limiting enzyme in the classical BA biosynthetic pathway was increased; while the expression of ileal fibroblast growth factor 15 (FGF‐15), the critical gut‐liver regulator of CYP7A1 and BA synthesis was repressed. In addition, serum TG levels were significantly decreased by 30% post‐GSPE administration. Based on our results, we propose that GSPE acts as an intestinal gene selective bile acid receptor modulator (BARM), thereby altering enterohepatic BA recirculation, which contributes to the TG‐lowering ability of this extract. Grant Funding Source: Supported by USDA‐Hatch NEV0738 and Multi‐state project W3122