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Evaluation of varying dietary cholesterol levels on the gene regulatory actions and physiological effects of a grape seed procyanidin extract
AuthorRoling, Brent Falcon
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Numerous rodent-based studies have repeatedly demonstrated that grape seed procyanidin extract (GSPE) exhibits hypocholesterolemic and hypolipidemic actions via mechanisms involving an interaction with the farnesoid x receptor (Fxr). In vitro studies revealed that GSPE acts as a co-agonist ligand for Fxr. In conjunction with chenodeoxycholic acid (CDCA), an endogenous Fxr ligand, GSPE differentially modulates gene regulatory mechanisms, compared to CDCA alone. GSPE, acting as a co-agonist ligand, modulates mechanisms of bile acid homeostasis to increase fecal bile acid excretion, in turn inducing the hepatic conversion of triglycerides and cholesterol into bile acids. Several in vivo studies have examined the hypolipidemic action of GSPE in the presence of varying experimental diets. These studies demonstrated that GSPE-induced modification of bile acid, triglyceride and cholesterol homeostatic mechanisms to reduce serum cholesterol and triglycerides in rodents fed a standard diet, and alleviated dyslipidemia associated with consumption of high-fat and high-fructose diets. Based on these findings, we hypothesized that GSPE would exhibit similar mechanisms of action in the presence of 0% and low cholesterol-containing diets, comparable to a standard chow diet, and also protect the body from dyslipidemia induced by high-cholesterol feeding. Therefore, forty-eight male C57BL/6 mice were fed either a 0%, 0.02%, 0.2%, or 2% cholesterol diet for four weeks (n=12/group). The groups were then split in half and each sub-group received either vehicle (water) or GSPE (250 mg/kg body weight) via oral gavage (n=6/treatment/group). Fourteen hours later, mice were sacrificed and blood, livers and intestines were harvested. Serum parameters, feces, hepatic histology, and hepatic and intestinal gene expression were analyzed. Both dietary cholesterol and GSPE had an effect on physiological and molecular aspects of bile acid, cholesterol and triglyceride homeostasis. Increased dietary cholesterol reduced cholesterolgenic gene expression, reduced bile acid transport and increased fecal bile acid excretion. The 2% cholesterol diet induced fecal cholesterol excretion, which was further increased by GSPE administration. In the presence of a diet containing low or zero dietary cholesterol, GSPE reduced serum bile acid and triglyceride levels, gene expression associated with intestinal cholesterol synthesis and transport, bile acid absorption and transport, as well as hepatic cholesterol and lipid synthesis. GSPE exhibited differential mechanistic regulation in the presence of high levels of dietary cholesterol. In the 2% cholesterol group, GSPE administration increased fecal cholesterol excretion and decreased fecal bile acid excretion, as well as serum cholesterol and non-esterified fatty acid levels. These physiological changes were accompanied by a reduction in intestinal gene expression associated with reverse cholesterol transport and cholesterol secretion, as well as hepatobiliary cholesterol secretion. GSPE administration also decreased hepatic triglyceride and cholesterol content in all diet groups. The protective effect is particularly important in the high-cholesterol diets, which induced hepatic steatosis. Collectively, these results demonstrate that in conditions of low dietary cholesterol, GSPE induces similar effects on bile acid transport and enterohepatic recirculation, as those observed in previous studies with standard chow diets. However, it appears that protective mechanisms associated with GSPE are altered in conditions of high dietary cholesterol. This project presents novel findings demonstrating that GSPE administration induces trans-intestinal cholesterol efflux (TICE) to protect the body from excess dietary cholesterol in states of high-cholesterol feeding. This is evidenced by decreased serum cholesterol and increased fecal cholesterol excretion, accompanied by a reduction in gene expression associated with hepatobiliary cholesterol secretion and reverse cholesterol transport.