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Cholesterol absorption and biosynthesis pathways. Dietary cholesterol entering the proximal intestinal lumen is composed of both cholesterol and CE. Cholesterol esterase catalyses the hydrolysis of CE to free cholesterol and contributes to the formation of lysolecithin-containing micelles. Cholesterol in micelles both from the dietary source and from hepatic cholesterol are subsequently available for uptake via the proximal intestinal lumen. Recent evidence suggests the process of cholesterol uptake is mediated by a protein transport mechanism and not a passive diffusion process, as evidenced by the kinetic processes involved, the sterol specifi city and the fact that the drug ezetimibe inhibits cholesterol uptake. Recently, this protein was identifi ed as NPC1L1 and has been shown to reside on the apical surface of the intestinal enterocytes. Cholesterol re-esterifi cation occurs within the enterocytes via ACAT and the cholesterol is packaged into chylomicrons and secreted into the lymph. Peripheral cells secrete FC and reprocessing occurs, resulting in the formation of antiatherogenic HDL and subsequently the atherogenic LDL and VLDL. Inhibition of this latter process by CETP inhibitors results in the accumulation of antiatherogenic HDL. Owing to the high amounts of NPC1L1 expression in the liver, it is likely that the cholesterol transporter contributes to the re-uptake of cholesterol from micelles in bile and this process is likely to be inhibited by ezetimibe. Simultaneously, the liver hepatocytes synthesise cholesterol via a complex process involving at least 30 enzymes. However, the target for cholesterol reduction in the liver is by the statins, by inhibition of the rate limiting enzyme HMG-CoA reductase.
Source publication
The relationship between serum cholesterol and coronary heart disease is well established. Inhibitors of endogenous cholesterol synthesis (statins) have been shown to reduce cardiovascular events. Similarly, strategies directed towards the gastrointestinal tract may also be effective, as cholesterol absorption via the intestinal lumen is known to c...
Citations
... The attempts to find natural bioactives effective at limiting the biosynthesis of cholesterol, for example, inhibitors of 3-hydroxy-3methylglutaryl coenzyme A reductase, have been relatively unsuccessful. Therefore, targeting cholesterol absorption processes is an alternative strategy to lower plasma cholesterol, particularly by the use of nutraceuticals or functional foods [20]. The benefits of this approach have already been demonstrated for a range of food products containing plant sterols and stanols [21]. ...
... Also, we could deplete cellular cholesterol stores by exposure of cells for a short period with MβCD, and the cholesterol could be rapidly restored after incubation in a cholesterol-containing medium as demonstrated previously [22]. We also observed that approximately 50% of cholesterol transport was ezetimibe sensitive (ezetimibe is a specific inhibitor of Niemann-Pick C1-like 1 cholesterol transporter), indicating that at least one component of the influx of cholesterol into the cells was via a specific cholesterol transport process, as shown previously [20,[33][34][35]. Finally, [ 3 H]cholesterol uptake could be blocked by a molar excess of free (unlabeled) cholesterol. ...
Accumulating evidence suggests that grape seed and wine polyphenol extracts possess a diverse array of actions and may be beneficial in the prevention of inflammatory-mediated disease such as cardiovascular disease and cancer. This study aimed to determine whether the reported pleiotropic effects of several polyphenolic extracts from grape seed products or red wine would also include inhibition of cholesterol uptake and cell proliferation, and inhibit a known specific target of the inflammatory process, that is, 5-lipoxygenase (5-LOX). Incubation of HT29, Caco2, HepG2, or HuTu80 cells in a medium containing [(3)H]cholesterol in the presence of a grape seed extract (GSE) or red wine polyphenolic compounds (RWPCs) inhibited [(3)H]cholesterol uptake by up to 66% (which appeared maximal). The estimated IC(50) values were 60 and 83 microg/mL for RWPC and GSE, respectively. Similar cholesterol uptake inhibitory effects were observed using the fluorescent cholesterol analogue NBD cholesterol. The inhibition of cholesterol uptake was independent of the sample's (GSE and RWPC) potent antioxidative capacity. Red wine polyphenolic compound and GSE dose dependently inhibited HT29 colon adenocarcinoma cell proliferation, which was accompanied by an increase in apoptosis. In addition, RWPC and GSE inhibited 5-LOX activity with the IC(50) values being 35 and 13 microg/mL, respectively. Two of 3 other GSEs tested also significantly inhibited 5-LOX activity. Inhibition of cholesterol uptake and proinflammatory 5-LOX activity may be beneficial in preventing the development of chronic degenerative diseases such as cardiovascular disease and cancer.
The aim of this review is to discuss the accumulating evidence that suggests that grape extracts and purified grape polyphenols possess a diverse array of biological actions and may be beneficial in the prevention of some inflammatory-mediated diseases including cardiovascular disease. The active components from grape extracts, which include the grape seed, grape skin, and grape juice, that have been identified thus far include polyphenols such as resveratrol, phenolic acids, anthocyanins, and flavonoids. All possess potent antioxidant properties and have been shown to decrease low-density lipoprotein-cholesterol oxidation and platelet aggregation. These compounds also possess a range of additional cardioprotective and vasoprotective properties including antiatherosclerotic, antiarrhythmic, and vasorelaxation actions. Although not exclusive, antioxidant properties of grape polyphenols are likely to be central to their mechanism(s) of action, which also include cellular signaling mechanisms and interactions at the genomic level. This review discusses some of the evidence favoring the consumption of grape extracts rich in polyphenols in the prevention of cardiovascular disease. Consumption of grape and grape extracts and/or grape products such as red wine may be beneficial in preventing the development of chronic degenerative diseases such as cardiovascular disease.
