Abstract
The objective of this study was to determine whether a grape seed procyanidin extract (GSPE) exerts a triglyceride-lowering effect in a hyperlipidemic state using the fructose-fed rat model and to elucidate the underlying molecular mechanisms. Rats were fed either a starch control diet or a diet containing 65% fructose for 8 weeks to induce hypertriglyceridemia. During the 9th week of the study, rats were maintained on their respective diet and administered vehicle or GSPE via oral gavage for 7 days. Fructose increased serum triglyceride levels by 171% after 9 weeks, compared to control, while GSPE administration attenuated this effect, resulting in a 41% decrease. GSPE inhibited hepatic lipogenesis via down-regulation of sterol regulatory element binding protein 1c and stearoyl-CoA desaturase 1 in the fructose-fed animals. GSPE increased fecal bile acid and total lipid excretion, decreased serum bile acid levels and increased the expression of genes involved in cholesterol synthesis. However, bile acid biosynthetic gene expression was not increased in the presence of GSPE and fructose. Serum cholesterol levels remained constant, while hepatic cholesterol levels decreased. GSPE did not modulate expression of genes responsible for esterification or biliary export of the newly synthesized cholesterol, but did increase fecal cholesterol excretion, suggesting that in the presence of GSPE and fructose, the liver may secrete more free cholesterol into the plasma which may then be shunted to the proximal small intestine for direct basolateral to apical secretion and subsequent fecal excretion. Our results demonstrate that GSPE effectively lowers serum triglyceride levels in fructose-fed rats after one week administration. This study provides novel insight into the mechanistic actions of GSPE in treating hypertriglyceridemia and demonstrates that it targets hepatic de novo lipogenesis, bile acid homeostasis and non-biliary cholesterol excretion as important mechanisms for reducing hypertriglyceridemia and hepatic lipid accumulation in the presence of fructose.
Highlights
Rates of obesity, type 2 diabetes, non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD) have increased significantly in recent years, both in children and adults [1,2,3,4]
We identified grape seed procyanidin extract (GSPE) as a co-agonist ligand for the farnesoid x receptor [22], a transcription factor that regulates bile acid (BA), TG, cholesterol and glucose homeostasis [23,24,25,26,27]
To explore the molecular mechanism underlying the hypotriglyceridemic effect of GSPE observed in the fructose-fed animals, we examined the expression of hepatic genes that regulate lipogenesis, cholesterol synthesis and transport, and BA synthesis and transport
Summary
Type 2 diabetes, non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD) have increased significantly in recent years, both in children and adults [1,2,3,4] This surge has correlated with a significant increase in dietary fructose intake in the United States, due in large part to the rise in consumption of sugar-sweetened beverages [5]. In contrast to fructose-induced metabolic dysregulation, evidence indicates that diets rich in fruits and vegetables, e.g. the Mediterranean diet, exert protective effects against the development of the metabolic syndrome [10]. Such diets tend to be high in flavonoids, which exhibit cardioprotective effects in humans [11, 12]. Evidence shows that GSPE administration increases fatty acid β-oxidation [19] and reduces VLDL-TG secretion [21]
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