Grape seed extract supplementation modulates hepatic lipid metabolism in rats. Implication of PPARβ/δ

In mammals, the liver is involved in nutrient metabolism and in the regulation of lipid and glucose homeostasis. Multiple studies have described improvements in liver disorders after regular consumption of grape seed extract (GSE). GSE prevents or ameliorates hepatic metabolic dysfunction through AMPK activation, which reduces hepatic lipogenesis while enhancing hepatic lipid oxidation. However, the involvement of ChREBPβ and PPARβ/δ in these effects has not been fully elucidated. We aim to demonstrate that chronic consumption of GSE at low doses (25 mg kg^-1 body weight per day) produces beneficial effects on hepatic glucose and lipid metabolism in young lean Wistar rats and that part of these effects involve ChREBPβ inactivation and PPARβ/δ activation. In our study, increased concentrations of structurally related (-)-(epi)catechin metabolites and 5-carbon ring fission metabolites were found in the serum of GSE-supplemented rats parallel with the reduction in triglycerides and leptin levels, hepatic cholesterol content and visceral adiposity. GSE supplementation inactivates ChREBP and GSK-3β, which has been linked to improvements in hepatic lipid and glucose metabolism. Furthermore, the consumption of GSE promotes the expression of Pparβ/δ, as well as Pgc-1α and Acox-1, which control hepatic lipid oxidation. Interestingly, pharmacological inhibition of PPARβ/δ slowed the induction of Pgc-1α and Acox-1, as well as the activation of AMPK triggered by GSE consumption. Our data suggest that PPARβ/δ activation is involved in the metabolic reprogramming effects of chronic GSE consumption in young rats, by modulating, at least, part of the transcriptional programs that maintain hepatic and systemic fuel homeostasis.