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Elucidating the Molecular Mechanisms Underlying the Hepatic Farnesoid X Receptor (FXR)-mediated Effects that Contribute to the Triglyceride-Lowering Ability of a Grape Seed Proceyanidin Extract
Agriculture, Veterinary and Rangeland Sciences
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Procyanidins are dietary flavonoids associated with reduced risk of cardiovascular disease, and function partially by reducing hypertriglyceridemia. Grape seed procyanidin extract (GSPE) was shown to decrease triglyceride levels via activation of the nuclear hormone receptor, farnesoid x receptor (FXR), thereby increasing small heterodimer partner (SHP) messenger ribonucleic acid (mRNA) expression, which then inhibits transcription of Sterol Regulatory Element Binding Protein 1c (SREBP-1c), a key transcription factor regulating lipogenic gene expression. The objective of this study is to further elucidate the molecular mechanism by which GSPE lowers triglyceride levels by assessing gene expression changes in mice 2 hours after an acute dose of GSPE. This knowledge will ultimately contribute to the development of a natural dietary treatment for hypertriglyceridemia. The results from this study indicate that at the 2 hour time point following GSPE administration there were no significant changes in mRNA expression for SHP (P=0.259), SREBP1c (P=0.192), or other SHP downstream target-genes that were analyzed. These results indicate that the cascade of molecular events leading to a lowering in serum triglyceride levels manifests later than 2 hours in the liver following GSPE administration. It is proposed that initial changes in gene expression are mediated in the intestine primarily, which then result in changes in gene expression in the liver at a later time point, such as 14 hours, as previously reported. Consequently, changes in hepatic gene expression following GSPE administration are likely to occur between 2 and 14 hours. These results help establish a profile of the changes in gene expression after GSPE administration, thereby aiding in the effort to further elucidate the molecular mechanism behind the triglyceride-lowering effect of GSPE.