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A Grape Seed Procyanidin Extract Ameliorates Fructose-Induced Hypertriglyceridemia in Rats via Enhanced Fecal Bile Acid and Cholesterol Excretion and Inhibition of Hepatic Lipogenesis.

Downing LE, Heidker RM, Caiozzi GC, Wong BS, Rodriguez K, Del Rey F, Ricketts ML - PLoS ONE (2015)

Bottom Line: Fructose increased serum triglyceride levels by 171% after 9 weeks, compared to control, while GSPE administration attenuated this effect, resulting in a 41% decrease.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Agriculture, Nutrition and Veterinary Sciences, University of Nevada Reno, Reno, Nevada, United States of America.

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.

No MeSH data available.


Hepatic expression of genes involved in bile acid biosynthesis and transport following treatments.Gene expression changes were analyzed for (A) Cyp7a1, (B) Cyp8b1, (C) Cyp27a1, (D) Cyp7b1, and (E) Abcb11. ** p<0.01.
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pone.0140267.g006: Hepatic expression of genes involved in bile acid biosynthesis and transport following treatments.Gene expression changes were analyzed for (A) Cyp7a1, (B) Cyp8b1, (C) Cyp27a1, (D) Cyp7b1, and (E) Abcb11. ** p<0.01.

Mentions: Based on the combined observations of reduced serum TG and BA levels and increased fecal BA excretion, we postulated that serum TG levels were reduced due to the need to synthesize cholesterol and then BAs. Therefore, we next examined potential regulatory effects on genes involved in both cholesterol and BA synthesis. Dietary fructose had no effect on the expression of 3-hydroxy-3-methylglutaryl-CoA synthase 1 (Hmgcs1), while GSPE significantly increased expression (Fig 5A). In addition, no changes in expression were seen in the fructose-fed animals with respect to 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr) (Fig 5B). However, GSPE increased expression of Hmgcr compared to both the control and fructose-vehicle-treated animals. In addition, several genes important in cholesterol synthesis were significantly upregulated in the presence of GSPE, including farnesyl-diphosphate farnesyltransferase 1 (Fdft1) (Fig 5C), squalene epoxidase (Sqle) (Fig 5D), lanosterol synthase (2,3-oxidosqualene-lanosterol cyclase) (Lss) (Fig 5E) and 7-dehydrocholesterol reductase (Dhcr7) (Fig 5F), indicating that there was increased cholesterol synthesis in the presence of GSPE. Consequently, we next evaluated the effects of GSPE on BA biosynthesis. No significant effects were seen with respect to cytochrome P450, family 7, subfamily A, polypeptide 1, (cholesterol 7 alpha-monooxygenase; Cyp7a1) expression, which initiates the classical (neutral) BA biosynthetic pathway, following GSPE administration (Fig 6A), while cytochrome P450, family 8, subfamily B, polypeptide 1, (sterol 12-alpha-hydroxylase; Cyp8b1) levels were significantly reduced (Fig 6B). We then assessed the effects of GSPE on genes involved in the alternative (acidic) BA biosynthesis pathway. No significant effects were observed with respect to cytochrome P450, family 27, subfamily A, polypeptide 1 (steroid 27-hydroxylase; Cyp27a1) (Fig 6C) or cytochrome P450, family 7, subfamily B, polypeptide 1 (oxysterol 7-alpha-hydroxylase; Cyp7b1) (Fig 6D). In addition, no changes were observed in the expression of ATP-binding cassette, sub-family B (MDR/TAP), member 11 (bile salt export pump; Abcb11) (Fig 6E).


A Grape Seed Procyanidin Extract Ameliorates Fructose-Induced Hypertriglyceridemia in Rats via Enhanced Fecal Bile Acid and Cholesterol Excretion and Inhibition of Hepatic Lipogenesis.

Downing LE, Heidker RM, Caiozzi GC, Wong BS, Rodriguez K, Del Rey F, Ricketts ML - PLoS ONE (2015)

Hepatic expression of genes involved in bile acid biosynthesis and transport following treatments.Gene expression changes were analyzed for (A) Cyp7a1, (B) Cyp8b1, (C) Cyp27a1, (D) Cyp7b1, and (E) Abcb11. ** p<0.01.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4601771&req=5

pone.0140267.g006: Hepatic expression of genes involved in bile acid biosynthesis and transport following treatments.Gene expression changes were analyzed for (A) Cyp7a1, (B) Cyp8b1, (C) Cyp27a1, (D) Cyp7b1, and (E) Abcb11. ** p<0.01.
Mentions: Based on the combined observations of reduced serum TG and BA levels and increased fecal BA excretion, we postulated that serum TG levels were reduced due to the need to synthesize cholesterol and then BAs. Therefore, we next examined potential regulatory effects on genes involved in both cholesterol and BA synthesis. Dietary fructose had no effect on the expression of 3-hydroxy-3-methylglutaryl-CoA synthase 1 (Hmgcs1), while GSPE significantly increased expression (Fig 5A). In addition, no changes in expression were seen in the fructose-fed animals with respect to 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr) (Fig 5B). However, GSPE increased expression of Hmgcr compared to both the control and fructose-vehicle-treated animals. In addition, several genes important in cholesterol synthesis were significantly upregulated in the presence of GSPE, including farnesyl-diphosphate farnesyltransferase 1 (Fdft1) (Fig 5C), squalene epoxidase (Sqle) (Fig 5D), lanosterol synthase (2,3-oxidosqualene-lanosterol cyclase) (Lss) (Fig 5E) and 7-dehydrocholesterol reductase (Dhcr7) (Fig 5F), indicating that there was increased cholesterol synthesis in the presence of GSPE. Consequently, we next evaluated the effects of GSPE on BA biosynthesis. No significant effects were seen with respect to cytochrome P450, family 7, subfamily A, polypeptide 1, (cholesterol 7 alpha-monooxygenase; Cyp7a1) expression, which initiates the classical (neutral) BA biosynthetic pathway, following GSPE administration (Fig 6A), while cytochrome P450, family 8, subfamily B, polypeptide 1, (sterol 12-alpha-hydroxylase; Cyp8b1) levels were significantly reduced (Fig 6B). We then assessed the effects of GSPE on genes involved in the alternative (acidic) BA biosynthesis pathway. No significant effects were observed with respect to cytochrome P450, family 27, subfamily A, polypeptide 1 (steroid 27-hydroxylase; Cyp27a1) (Fig 6C) or cytochrome P450, family 7, subfamily B, polypeptide 1 (oxysterol 7-alpha-hydroxylase; Cyp7b1) (Fig 6D). In addition, no changes were observed in the expression of ATP-binding cassette, sub-family B (MDR/TAP), member 11 (bile salt export pump; Abcb11) (Fig 6E).

Bottom Line: Fructose increased serum triglyceride levels by 171% after 9 weeks, compared to control, while GSPE administration attenuated this effect, resulting in a 41% decrease.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Agriculture, Nutrition and Veterinary Sciences, University of Nevada Reno, Reno, Nevada, United States of America.

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.

No MeSH data available.