title: A Grape Seed Procyanidin Extract Ameliorates Fructose-Induced Hypertriglyceridemia in Rats via Enhanced Fecal Bile Acid and Cholesterol Excretion and Inhibition of Hepatic Lipogenesis.
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.
authors.affiliation: Department of Agriculture, Nutrition and Veterinary Sciences, University of Nevada Reno, Reno, Nevada, United States of America.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Downing
authors.affiliation: Department of Agriculture, Nutrition and Veterinary Sciences, University of Nevada Reno, Reno, Nevada, United States of America.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Heidker
authors.affiliation: Department of Agriculture, Nutrition and Veterinary Sciences, University of Nevada Reno, Reno, Nevada, United States of America.
authors.forename: Gianella C
authors.initials: GC
authors.lastname: Caiozzi
authors.affiliation: Department of Agriculture, Nutrition and Veterinary Sciences, University of Nevada Reno, Reno, Nevada, United States of America.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Wong
authors.affiliation: Department of Agriculture, Nutrition and Veterinary Sciences, University of Nevada Reno, Reno, Nevada, United States of America.
authors.forename: Kelvin
authors.initials: K
authors.lastname: Rodriguez
authors.affiliation: Department of Agriculture, Nutrition and Veterinary Sciences, University of Nevada Reno, Reno, Nevada, United States of America.
authors.forename: Fernando
authors.initials: F
authors.lastname: Del Rey
authors.affiliation: Department of Agriculture, Nutrition and Veterinary Sciences, University of Nevada Reno, Reno, Nevada, United States of America.
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Ricketts
mesh_terms: D000818:Animals; D044946:Biflavonoids / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000096:biosynthesis / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D001835:Body Weight / Q000187:drug effects; D002392:Catechin / Q000494:pharmacology*; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism; D004032:Diet / Q000009:adverse effects; D005243:Feces / Q000737:chemistry*; D005632:Fructose / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D056604:Grape Seed Extract / Q000737:chemistry*; D015228:Hypertriglyceridemia / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D050155:Lipogenesis / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D044945:Proanthocyanidins / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014280:Triglycerides / Q000097:blood
chemical_list: D044946:Biflavonoids; D001647:Bile Acids and Salts; D056604:Grape Seed Extract; D000960:Hypolipidemic Agents; D044945:Proanthocyanidins; D014280:Triglycerides; D005632:Fructose; C017674:procyanidin; D002392:Catechin; D002784:Cholesterol