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Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269
2To whom correspondence should be addressed. E-mail: maria-luz.fernandez{at}uconn.edu.
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ABSTRACT |
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 TOP ABSTRACT Polyphenols and Hepatic...Polyphenols and Plasma Lipids.Polyphenols and Inflammatory...Summary.LITERATURE CITED |
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KEY WORDS: • dietary polyphenols • lipoprotein metabolism • cytokines • coronary heart disease • inflammation
Polyphenols and related compounds can be found in every plant species. In plants, polyphenols are important for pigmentation, reproduction, growth, and protection against pathogens. In industry, polyphenols are used in the production of paints, paper, and cosmetics as well as in food additives (1). However, in more recent years, polyphenols have received much attention in disease treatment and prevention due to their antioxidant capabilities.
Currently, there are >8000 known polyphenolic structures (1). Polyphenols share a common chemical structure and differ only in their additional linkages with other compounds. The majority of polyphenols have a sugar residue linked to the carbon skeleton. Glucose is a common sugar residue; however, residues can include different monosaccharides, disaccharides, or oligosaccharides. Other compounds including amines, organic acids, carboxylic acids, lipids, and other polyphenols may also be linked to the basic polyphenolic structure (1).
Because of the abundance of polyphenols in nature, it is not surprising that they can be found in fruits, vegetables, coffee, tea, chocolate, and soy (2). Once ingested, polyphenols have several possible fates, including absorption in the small intestine or colon, and/or excretion in the feces or urine. The site and rate of absorption depend on the chemical structure, degree of glycosylation/acylation, conjugation of other phenolics, molecular size, degree of polymerization, and solubility (1,2). In the small intestine, polyphenols can enter the mucosa through passive diffusion. In some instances, hydrophobic moieties must be cleaved for absorption to take place. In the colon, polyphenols are initially digested into smaller phenolic structures by gut microflora. After this initial digestion is complete, the polyphenols and their metabolites may be absorbed (1).
Once absorption has taken place, polyphenols and their metabolites are transported to the liver. Further digestion may occur there, and then polyphenol metabolites may be transported to extrahepatic tissues or to the kidneys where they are excreted in the urine. For the majority of polyphenols, the maximum concentration in the plasma is apparent 1–2 h after ingestion. Polyphenols may also be incorporated into bile, returned to the small intestine, and eventually be excreted in the feces (1).
Polyphenols have generated a great amount of scientific research due to their in vivo and in vitro antioxidant capabilities. For years, red wine was thought to have beneficial effects on cardiovascular health. This relation was clear in the French Paradox phenomenon as well as in the Mediterranean diet. The French Paradox is defined as a low incidence of coronary heart disease (CHD)3 while consuming a diet rich in saturated fat. The Mediterranean diet, rich in fruits and wine, was shown to protect against the occurrence of coronary events (3,4). In addition, the inclusion of fruits and vegetables in the diet may help reverse hyperlipidemia, alter the atherogenicity of the LDL particle (5), and protect the cholesterol in LDL from oxidation (6). For example, grapes are comprised of a wide variety of polyphenols including resveratrol (stilbene), flavonoids and its derivatives, flavons, flavonols, and anthocyanins. Polyphenols can be found in grape seeds as well as in the skin. The concentration of these compounds varies due to climate and therefore variety of grape.
In general, more than two thirds of the polyphenols consumed in the diet are flavonoids (7). The majority of flavonoid and polyphenol research has focused on the reduction of LDL oxidation in vivo and in vitro. Therefore, the following is a review of the effects of polyphenols on lipid metabolism and inflammation in both in vivo and in vitro models.
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Polyphenols and Hepatic Cholesterol Metabolism. |
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TOPABSTRACTPolyphenols and Hepatic...Polyphenols and Plasma Lipids.Polyphenols and Inflammatory...Summary.LITERATURE CITED |
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In examining lipoprotein production, the majority of polyphenol research has addressed their effects on hepatic production of lipoproteins. The citrus flavonoids, naringenin and hesperitin, were shown to reduce apo B secretion in hepatocytes (13,14). This effect was associated with a reduction in cholesteryl ester (CE) mass, a selective decrease in acyl-CoA cholesterol acyltransferase (ACAT2), and microsomal transfer protein (MTP) mRNA abundance accompanied by a decrease in MTP activity. In addition to these findings, naringenin reduced triglyceride (TG) secretion into the medium. Dealcoholized red wine treatment was also shown to reduce apo B-100 secretion from Hep G2 cells up to 50% (15). Reductions in intracellular CE, FC, and TC concentrations were also apparent after treatment. Similarly, in ovariectomized guinea pigs, a model for menopause, treatment with lyophilized grape powder (LGP) significantly lowered hepatic CE concentrations while significantly increasing FC concentrations compared with control guinea pigs (16). The significant alterations in hepatic cholesterol pools were accompanied by a 27% decrease in hepatic ACAT activity.
The mechanism by which polyphenols reduce hepatic apo B production may be through their binding with the plasma membrane transport P-glycoprotein, which inhibits cholesterol esterification (17), decreasing the incorporation of CE into nascent VLDL. A lower apo B production rate is strongly correlated with reduced hepatic ACAT activity in miniature pigs (18) and in African green monkeys (19).
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Polyphenols and Plasma Lipids. |
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TOPABSTRACTPolyphenols and Hepatic...Polyphenols and Plasma Lipids.Polyphenols and Inflammatory...Summary.LITERATURE CITED |
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In ovariectomized guinea pigs, LGP treatment reduced VLDL cholesterol (VLDL-C) and TG by 50 and 39% compared with the control (16). Furthermore, golden Syrian hamsters fed red wine phenolics had a significant decrease in plasma apo B concentrations (22). Recently in our laboratory, the same LGP used in the guinea pig study was shown to significantly decrease TG, apo B, apo E, and LDL cholesterol (LDL-C) concentrations in both pre- and postmenopausal women (23). Similar to our previous study, grape polyphenols may have altered hepatic secretion of TG-rich VLDL. This reduction is evident when observing the decreases in both plasma apo B and apo E concentrations. The significant decrease in apo E concentrations may have further reduced plasma TG concentrations. In general, apo E displaces apo C-II from the VLDL particle, thereby inhibiting lipoprotein lipase (LPL) activity and overall lipolysis. Furthermore, Huang et al. (24) showed that adding apo C-II to transgenic apo-E3–enriched VLDL increased LPL activity in a dose-dependent manner. The reductions in apo E and TG concentrations suggest less displacement by apo E, thereby promoting LPL activity and further reducing plasma TG concentrations.
Due to decreases in TG concentrations, LGP treatment was shown to affect overall lipoprotein metabolism. Decreased concentrations of plasma TG altered substrate availability in the delipidation cascade, leading to the observed decrease in LDL-C concentrations. After the 4-wk treatment period, the LGP treatment induced a significant decrease in cholesteryl ester transfer protein (CETP) activity as well. This decrease in CETP activity may be due in part to the substantial decrease in substrate availability including both plasma TG and LDL-C.
It is evident that grape polyphenols modify the packaging of VLDL through alteration in hepatic enzyme activity and apo B secretion. These modifications seem to decrease the overall secretion of the VLDL particles and therefore, decrease plasma TG and related apo concentrations. Due to alterations in TG substrate, further modifications in lipoprotein metabolism may occur.
The alteration in TG metabolism may not be the single mechanism driving the hypocholesterolemic effects of grape polyphenols. When golden Syrian hamsters were treated with dealcoholized red wine, red wine, or grape juice, similar significant reductions in both TC and LDL-C concentrations were apparent in all treatment groups compared with the control (25). Although there was a trend for a decrease in TG concentrations in all treatment groups compared with the control, the differences were not significant. That study, along with others, suggests the presence of an additional mechanism by which grape polyphenols exert a cardioprotective effect. In Hep G-2 cells, dealcoholized red wine was shown to significantly upregulate LDL receptor activity (15). This significant increase in activity was similar to the increase seen when Hep G-2 cells were treated with atorvastatin. Furthermore, when Hep G-2 cells were treated with increasing doses of red wine, LDL receptor mRNA abundance was significantly increased in a dose-responsive manner. The increase in LDL receptor activity and abundance may be a result of the homeostatic intracellular cholesterol feedback loop. In general, a decrease in intracellular cholesterol will upregulate LDL receptor expression and activity, whereas an increase in intracellular cholesterol will downregulate the receptor (26). Grape polyphenols were shown to alter hepatic cholesterol concentrations; therefore, the liver compensates for this deficit by upregulating the LDL receptor and an overall decrease in plasma LDL concentrations occurs. A diagram showing the major sites of action of dietary polyphenols is given in Figure 1.
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Polyphenols and Inflammatory Cytokines. |
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TOPABSTRACTPolyphenols and Hepatic...Polyphenols and Plasma Lipids.Polyphenols and Inflammatory...Summary.LITERATURE CITED |
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and interleukin (IL)-6 concentrations in both pre- and postmenopausal women (23). Furthermore, in an 11-wk study with a crossover design comparing red wine and gin consumption in healthy men, adhesion molecules and monocyte adhesion to endothelial cells were significantly altered due to red wine (27). After the 4-wk period of red wine consumption, concentrations of the adhesion molecules including very-late activation antigen (VLA-4), lymphocyte-associated function antigen (LFA-1), Mac-1, and monocyte chemoattractant protein (MCP-1) on monocytes and T-lymphocytes, were significantly decreased compared with baseline (P < 0.05). The soluble cellular adhesion molecules (CAMs), ICAM-1 and VCAM-1, were decreased by 9 and 17%, respectively (27). Similarly, monocyte adhesion to TNF-–stimulated endothelial cells was also significantly decreased after red wine intake (28). Red wine intake was also shown to decrease MCP-1 after balloon injury to the abdominal aorta in cholesterol-fed rabbits. Furthermore, MCP-1 mRNA reduction paralleled decreases seen in aortic thickening in rabbits consuming the red wine (29). In both studies, although researchers concluded that alterations in monocyte adhesion molecules and CAMs affected the overall adhesion of monocytes to endothelial cells, they did not elaborate on the exact mechanism.
Suppression of the transcription factor, nuclear factor-
B (NF-B), was suggested to play a role in this mechanism. NF-B is responsible for activating cytokines, adhesion molecules, and procoagulant proteins (30). When activated, these inflammatory proteins can in turn increase NF-B levels and continue this cycle. It is important to note that oxidized LDL and other reactive oxygen species are also potent stimulators of NF-B (31). Red wine intake was also shown to decrease NF-B concentrations in monocytes. Healthy subjects were given a fat-enriched meal with or without red wine. The fat-enriched meal alone increased the expression of NF-B, whereas the red wine meal significantly decreased expression of NF-B (P < 0.05). The authors suggested that red wine polyphenols may have inhibited oxidation, thereby decreasing the activation of NF-B.
Resveratrol, a stilbene found in grapes, was found to affect a mechanism other than the inhibition of the NF-B pathway. The tyrosine kinase second messenger system is crucial in the regulation of the expression of CAMs and other cytokines. Resveratrol is a natural tyrosine kinase inhibitor. Therefore, researchers suggest that resveratrol affects the expression of inflammatory cytokines and adhesion molecules through its inhibition of NF-B as well as through inhibition of the tyrosine kinase system (32). A summary of the effects of polyphenols in inflammation is presented in Figure 2.
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Summary. |
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TOPABSTRACTPolyphenols and Hepatic...Polyphenols and Plasma Lipids.Polyphenols and Inflammatory...Summary.LITERATURE CITED |
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FOOTNOTES |
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3 Abbreviations used: ACAT, acyl-CoA cholesterol acyltransferase; apo, apolipoprotein; CAMs, cellular adhesion molecules; CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; CHD, coronary heart disease; FC, free cholesterol; IL, interleukin; LDL-C, LDL cholesterol; LFA-1, lymphocyte-associated function antigen; LGP, lyophilized grape powder; LPL, lipoprotein lipase; MCP-1, monocyte chemoattractant protein; MTP, microsomal transfer protein; NF-B, nuclear factor-B; TC, total cholesterol; TNF, tumor necrosis factor; TG, triglyceride; VLA-4, very-late activation antigen; VLDL-C, VLDL cholesterol.
Manuscript received 16 June 2005.
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LITERATURE CITED |
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TOPABSTRACTPolyphenols and Hepatic...Polyphenols and Plasma Lipids.Polyphenols and Inflammatory...Summary.LITERATURE CITED |
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