Data suggest that intestinal carotenoid absorption is a facilitated process. The present study was conducted to determine whether carotenoids and cholesterol share common pathways (transporters) for their intestinal absorption. Differentiated Caco-2 cells on membranes were incubated (16 h) with a carotenoid (1 micromol/L) with or without ezetimibe (EZ; Zetia, an inhibitor of cholesterol transport), and with or without antibodies against the receptors, cluster determinant 36 (CD36) and scavenger receptor class B, type I (SR-BI). Carotenoid transport in Caco-2 cells (cellular uptake + secretion) was decreased by EZ (10 mg/L) as follows: beta-carotene approximately alpha-carotene (50% inhibition) >> beta-cryptoxanthin approximately lycopene (20%) >> lutein:zeaxanthin (1:1) (7%). EZ reduced cholesterol transport by 31%, but not retinol transport. beta-Carotene transport was also inhibited by anti-SR-BI, but not by anti-CD36. The inhibitory effects of EZ and anti-SR-BI on beta-carotene transport were additive, indicating that they may have different targets. Finally, differentiated Caco-2 cells treated with EZ showed a significant decrease in mRNA expression for the surface receptors SR-BI, Niemann-Pick type C1 Like 1 protein (NPC1L1), and ATP-binding cassette transporter, subfamily A (ABCA1) and for the nuclear receptors retinoid acid receptor (RAR)gamma, sterol-regulatory element binding proteins (SREBP)-1 and -2, and liver X receptor (LXR)beta as assessed by real-time PCR analysis. The data indicate that 1) EZ is an inhibitor of carotenoid transport, an effect that decreases with increasing polarity of the carotenoid molecule, 2) SR-BI is involved in carotenoid transport, and 3) EZ may act, not only by interacting physically with cholesterol transporters as previously suggested, but also by downregulating expression of these proteins. The cellular uptake and efflux of carotenoids, like that of cholesterol, likely involve more than one transporter.
Inflammatory bowel diseases (IBD) arise from multiple causes, including environmental factors, gut microflora, immunity, and genetic predispositions. In the course of IBD, immune homeostasis and intestinal mucosa barrier integrity are impaired. Among natural preventive treatments that have been identified to date, polyphenols appear as promising candidates. They have been shown to protect against several diseases, including cardiovascular diseases and cancers, and they have anti-inflammatory properties in non-intestinal models. This paper will review the literature that has described to date some effects of polyphenols on intestinal inflammation. Studies, conducted using in vivo and in vitro models, provide evidence that pure polyphenolic compounds and natural polyphenolic plant extracts can modulate intestinal inflammation.
Recent studies support beneficial effects of polyphenols in various chronic inflammatory diseases, for example, the inflammatory bowel diseases. Inhibition of NF-kB activation by polyphenols could explain part of their anti-inflammatory properties, but few data are available on the intestine. The purpose of the present study was thus to investigate the effects of some polyphenols on NF-kB activation using human intestinal Caco-2 cells. Effects of standard polyphenols (50 mmol/l) were studied on different cellular events associated with NF-kB activation: (i) NF-kB activity using cells transiently transfected with a NF-kB -luciferase construct and stimulated by inflammatory agents (IL-1b, TNF-a or lipopolysaccharides (LPS)); (ii) phosphorylation of the inhibitor of kB (IkB-a) analysed by Western blot; (iii) secretion of IL-8 quantified by ELISA assay. Results showed that chrysin and ellagic acid inhibited NF-kB activity, whereas genistein and resveratrol increased it. These effects were independent of the nature of the inducer, indicating that polyphenols may modulate NF-kB activation by acting on a common event to the cytokine-and LPSmediated cascades. Chrysin strongly reduced (2·5-fold) IL-1b-induced IkB-a phosphorylation, whereas ellagic acid increased it (1·7-fold). Ellagic acid, genistein and epigallocatechin gallate reduced (4-to 8-fold) IL-1b-induced IL-8 secretion, while resveratrol promoted (1·7-fold) the secretion. Chrysin also diminished IL-8 secretion by 1·6-fold (but P. 0·05). The data indicate that polyphenols can modulate the NF-kB activation pathway in the intestine. Chrysin could block NF-kB activation via the inhibition of IkB-a phosphorylation. The other molecular targets of the active polyphenols are still to be identified.
The purpose of this study was to investigate the mechanisms by which carotenoids [xanthophylls vs. bcarotene (b-C)] are taken up by retinal pigment epithelial (RPE) cells. The human RPE cell line, ARPE-19, was used. When ARPE-19 cells were fully differentiated (7-9 weeks), the xanthophylls lutein (LUT) and zeaxanthin (ZEA) were taken up by cells to an extent 2-fold higher than b-C (P , 0.05). At 9 weeks, cellular uptakes were 1.6, 2.5, and 3.2%, respectively, for b-C, LUT, and ZEA. Similar extents were observed when carotenoids were delivered in either Tween 40 or "chylomicrons" produced by Caco-2 cells. Differentiated ARPE-19 cells did not exhibit any detectable b-C 15,15′-oxygenase activity or convert exogenous b-C into vitamin A. When using specific antibodies against the lipid transporters cluster determinant 36 (CD36) and scavenger receptor class B type I (SR-BI), cellular uptake of b-C and ZEA were significantly decreased (40-60%) with anti-SR-BI but not with anti-CD36. Small interfering RNA transfection for SR-BI led to marked knockdown of SR-BI protein expression (?90%), which resulted in decreased b-C and ZEA uptakes by 51% and 87%, respectively. Thus, the present data show that RPE cells preferentially take up xanthophylls versus the carotene by a process that appears to be entirely SR-BI-dependent for ZEA and partly so for b-C. This mechanism may explain, in part, the preferential accumulation of xanthophylls in the macula of the retina.-During, A., S. Doraiswamy, and E. H. Harrison. Xanthophylls are preferentially taken up compared with b-carotene by retinal cells via a SRBI-dependent mechanism.
These results show for the first time the direct neuroprotection of photoreceptors by xanthophylls and suggest that ZEA and LUT, along with DHA, are important environmental influences that together promote photoreceptor survival and differentiation.
In presence of oleate and taurocholate, differentiated CaCo-2 cell monolayers on membranes were able to assemble and secrete chylomicrons. Under these conditions, both cellular uptake and secretion into chylomicrons of  -carotene (  -C) were curvilinear, time-dependent (2-16 h), saturable, and concentration-dependent (apparent K m of 7-10 M) processes. Under linear concentration conditions at 16 h incubation, the extent of absorption of all-trans  -C was 11% (80% in chylomicrons), while those of 9-cis-and 13-cis- -C were significantly lower (2-3%). The preferential uptake of the all-trans isomer was also shown in hepatic stellate HSC-T6 cells and in a cell-free system from rat liver (microsomes), but not in endothelial EAHY cells or U937 monocyte-macrophages. Moreover, extents of absorption of ␣ -carotene ( ␣ -C), lutein (LUT), and lycopene (LYC) in CaCo-2 cells were 10%, 7%, and 2.5%, respectively. Marked carotenoid interactions were observed between LYC/  -C and  -C/ ␣ -C. The present results indicate that  -C conformation plays a major role in its intestinal absorption and that cis isomer discrimination is at the levels of cellular uptake and incorporation into chylomicrons. Moreover, the kinetics of cellular uptake and secretion of  -C, the inhibition of the intestinal absorption of one carotenoid by another, and the cellular specificity of isomer discrimination all suggest that carotenoid uptake by intestinal cells is a facilitated process. -During, A., M. M. Hussain, D. W. Morel, and E. H. Harrison. Carotenoid uptake and secretion by CaCo-2 cells:  -carotene isomer selectivity and carotenoid interactions. J.
The purpose of this study was to compare the mechanisms of intestinal retinol (ROL) and carotenoid transport. When differentiated Caco-2 cells were incubated with ROL for varying times, cellular ROL plateaued within 2 h, whereas retinyl ester (RE) formation increased continuously. ROL and RE efflux into basolateral medium (BM) increased linearly with time, ROL in the nonlipoprotein fraction and REs in chylomicrons (CMs). In contrast to carotenoids, ROL uptake was proportional to ROL concentration (0.5-110 mM). ROL efflux into BM occurred via two processes: a) a saturable process at low concentrations (,10 mM) and b) a nonsaturable process at higher concentrations. When ROL-loaded cells were maintained on retinoid-free medium, free ROL, but not REs, was secreted into BM. Glyburide significantly reduced ROL efflux but not ROL uptake. Inhibition of ABCA1 protein expression by small interfering RNAs decreased ROL efflux but not carotenoid efflux. Scavenger receptor class B type I (SR-BI) inhibition did not affect ROL transport but decreased carotenoid uptake. The present data suggest that a) ROL enters intestinal cells by diffusion, b) ROL efflux is partly facilitated, probably by the basolateral transporter ABCA1, and c) newly synthesized REs, but not preformed esters, are incorporated into CM and secreted. In contrast to ROL transport, carotenoid uptake is mediated by the apical transporter SR-BI, and carotenoid efflux occurs exclusively via their secretion in CM.-During, A., and E. H. Harrison. Vitamin A [or retinol (ROL)] is an essential fat-soluble nutrient required by humans for vision, cellular differentiation, development and growth, reproduction, and immunity (1). The de novo synthesis of vitamin A is limited to plants and microorganisms. Thus, humans must obtain vitamin A from the diet, either as preformed ROL or as provitamin A carotenoid precursors. Both deficiency and excess of vitamin A are known to cause pathologies. Vitamin A deficiency is usually a result of malnutrition but can also be attributable to abnormalities in the intestinal absorption of ROL or provitamin A carotenoids. Vitamin A deficiency especially affects children (100 to 140 million) in .100 countries (2). Vitamin A excess, although not as common as deficiency, is a result of excessive supplementation. Therefore, better knowledge about the mechanisms of absorption of vitamin A is important in determining the appropriate amounts of vitamin A required by humans.Vitamin A is present in the diet as retinyl esters (REs) found in foods of animal origin and as provitamin A carotenoids (mainly b-carotene, a-carotene, and b-cryptoxanthin) found in plant-derived products. Intestinal absorption of vitamin A from these dietary compounds requires several enzymatic steps. The hydrolysis of dietary REs in the intestinal lumen is catalyzed by enzymes such as the pancreatic triglyceride (TG) lipase and the intestinal brush border phospholipase B to yield unesterified ROL, which is the form absorbed into the intestinal mucosal cell. Some of th...
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