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Understanding the role of the intestine in the molecular hypotriglyceridemic actions of a grape seed procyanidin extract
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Hypertriglyceridemia is a prevalent condition that is associated with cardiovascular disease. Grape seed procyanidin extract (GSPE), a natural compound rich in procyanidins, has recently been shown to reduce serum triglyceride (TG) levels <italic>in vivo</italic> in normolipidemic animals. This effect was shown to be mediated via farnesoid X receptor (FXR), a member of the nuclear hormone receptor (NHR) superfamily. NHRs are ligand-inducible, and in some cases ligand-independent, transcription factors that interact with DNA to regulate gene expression. Activation of FXR by its endogenous ligand, bile acids (BA), modulates TG and BA homeostasis via regulation of hepatic and intestinal gene expression. Activation of FXR in the liver by BAs increases the expression of small heterodimer partner (SHP), which then acts as a repressor to decrease hepatic expression of sterol response element binding protein 1c (SREBP1c), a key transcription factor regulating lipogenic gene expression, thereby lowering serum TG levels. Studies have shown that in the liver, GSPE acts as a co-agonist ligand for FXR resulting in enhancement of BA-bound FXR activation <italic>in vitro</italic>, and that the TG-lowering ability of GSPE is lost <italic>in vivo</italic> in both, FXR and SHP knockout mouse models. Recently, utilizing a FXRE-luciferase reporter mouse model, it was shown that the intestine has the highest bile acid-induced FXR signaling under physiological conditions. FXR activation in the intestine induces the expression of several FXR target-genes including intestinal bile acid-binding protein (IBABP), organic solute transporters αβ (OSTαβ), and fibroblast growth factor (FGF) 15/19, while repressing the expression of the apical sodium dependent bile acid transporter (ASBT), which contributes to bile acid enterohepatic recirculation and bile acid homeostasis.The overall aim of this research was to further investigate the effects of GSPE to aid in the understanding of its molecular hypotriglyceridemic mode of action. Based on the fact that FXR is a bridge between the liver and the intestine to control bile acid levels and to regulate bile acid synthesis and enterohepatic flow, the first aim was to discern whether or not GSPE exerts any effects on intestinal FXR which could then contribute to the TG-lowering effect of GSPE. Therefore, the effects of GSPE on the regulation of known FXR target-genes in the intestine was investigated, to provide further insight into the inter-relationship between the intestine and the liver in the regulation of lipid homeostasis by GSPE. Studies have previously established the ability of GSPE to lower serum TG levels in a normolipidemic state, therefore, the second aim was to determine the potential of GSPE to lower serum TG levels in a hypertriglyceridemic state, and to identify the underlying molecular events. Our results indicate that in the intestine, GSPE may act as a gene-selective bile acid receptor modulator (BARM), rather than a bile acid-dependent co-agonist of FXR, as previously reported to occur in the liver. In the course of the studies conducted herein, GSPE treatment resulted in alterations in the expression of ileal FXR-target genes in different ways, i.e., GSPE acted as a FXR co-agonist thereby suppressing ASBT gene expression, while in contrast it acted a FXR modulator by decreasing CDCA-induced IBABP and OSTαβ, mRNA expression. Therefore, these results indicate that GSPE may impair bile acid enterohepatic recirculation, which is achieved by decreasing the intestinal up-take of bile acids, as well as by decreasing the amount of BA that return to the liver via the portal circulation. Furthermore, GSPE also induced a rapid and transit increase in FGF19 expression <italic>in vitro</italic> in Caco2 cells. We hypothesize that the above-mentioned effects induced by GSPE on intestinal FXR-target gene expression may therefore be contributing to changes in overall body BA homeostasis and also its serum TG lowering ability. Additionally, our results show that GSPE treatment effectively reduces serum TG levels by 27% when assessed in a fructose-fed rat model representing a hypertriglyceridemic state. Consequently, GSPE may represent a promising natural compound for the treatment of hypertriglyceridemia and its' related conditions.