Grape-seed proanthocyanidin extract (GSPE) modulates diurnal oscillations of key hepatic metabolic genes and metabolites alleviating hepatic lipid deposition in cafeteria-fed obese rats in a time-of-day-dependent manner

Abstract

Metabolic syndrome (MS) and its related diseases, including obesity and non-alcoholic fatty liver disease (NAFLD), have become a public health issue due to their increasing prevalence. Polyphenols, such as grape seed proanthocyanidin extract (GSPE), are bioactive compounds present in fruits and vegetables that show promise for MS treatment. We have previously demonstrated that the efficacy of this phenolic extract in the modulation of liver circadian clocks was affected by the time of the day at which it was ingested. Thus, we wondered if the beneficial effects of GSPE consumption in NAFLD could be mediated by diurnal modulation of hepatic lipid and glucose metabolism and whether GSPE effects on liver metabolism are impacted by the timing of administration. Results from hepatic lipid profiling, expression rhythm analysis of metabolic genes together with liver metabolomics in rats revealed that the CAF diet impaired glucose homeostasis and enhanced lipogenesis in the liver, leading to the generation of hepatosteatosis. Chronic consumption of GSPE at the onset of the active phase was able to restore the daily oscillation of liver mass and of key lipogenic and glycogenic genes, along with the reestablishment of liver metabolite rhythms, demonstrating hepatoprotective properties by decreasing triglyceride accumulation and lipid droplet formation in the liver, thus mitigating the development of CAF-induced NAFLD. Furthermore, in vitro data suggest that catechin, one of the main phenolic compounds found in the GSPE extract, may be involved in the ameliorating effects of GSPE against NAFLD.