Abstract
Dietary procyanidins are beneficial for maintaining health. Grape seed procyanidin extract (GSPE) in particular has been shown to regulate cholesterol and triglyceride (TG) homeostasis in vivo (1–5). We have identified several underlying molecular mechanisms by which GSPE decreases serum TG levels, including farnesoid x receptor (FXR)‐dependent decreased hepatic triglyceride synthesis, inhibition of enterohepatic bile acid recirculation and increased hepatic TG catabolism (3–5). Furthermore, we identified GSPE as a histone deacetylase (HDAC) inhibitor, leading to enhanced peroxisome proliferator‐activated receptor alpha (PPARα) target‐gene transcription and increased fatty acid β‐oxidation (6). During our initial investigations we discovered that GSPE acts as a co‐agonist ligand for FXR (2). The present study was designed as a follow‐up to this initial observation and aimed to identify which component (or components) within GSPE are responsible for the observed FXR‐dependent co‐agonist activity. GSPE was fractionated by column chromatography to separate compounds based on molecular size (n=3). The degree of polymerization for each fraction was determined by high performance liquid chromatography. Using a cell‐based transient transfection assay, each fraction was tested in combination with the bile acid, chenodeoxycholic acid (CDCA), to assess its ability to increase FXR transactivation (n=3, analyzed in triplicate), and compared to the effect seen with GSPE. Five different fractions from each column consistently enhanced FXR transactivation and were subsequently analyzed by mass spectrometry (MS). The MS results show that the fractions that enhance FXR transactivation are enriched in dimers and dimer gallates. Ultimately, this study facilitates enhanced understanding regarding the observed GSPE‐mediated FXR‐dependent regulatory effects on metabolic homeostasis observed in vivo.Support or Funding InformationUSDA NIFA Hatch Project NEV0738; USDA NIFA Multi‐state Project W‐3122: Beneficial and adverse effects of natural chemicals on human health and food safety; USDA NIFA Hatch Project NEV0749; A grant from the National Institute of General Medical Sciences (P20GM103440) from the National Institutes of Health.
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