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Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

Lycopene Absorption in Human Intestinal Cells and in Mice Involves Scavenger Receptor Class B Type I but Not Niemann-Pick C1-Like 1^1,2

³ Institut National de la Recherche Agronomique, UMR1260 Nutriments Lipidiques et Prévention des Maladies Métaboliques, F–13385 Marseille, France; ⁴ Institut National de la Santé et de la Recherche Médicale, U476, F–13385 Marseille, France; ⁵ Université Aix-Marseille 1, Univ Aix-Marseille 2, Faculté de Médecine, Institut de Physiopathologie Humaine de Marseille-Institut Fédératif de Recherche 125, F–13385 Marseille, France; ⁶ INSERM, U563 Centre de Physiopathologie de Toulouse Purpan, Département Lipoprotéines et Médiateurs Lipidiques, IFR30 and Université Paul Sabatier, F–31024 Toulouse, France; and ⁷ Friedrich Schiller University Jena, Institute of Nutrition, 07743 Jena, Germany

^* To whom correspondence should be addressed. E-mail: patrick.borel{at}univmed.fr.

	ABSTRACT

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
Cholesterol membrane transporters [scavenger receptor class B type I (SR-BI) and (cluster determinant 36) are involved in intestinal uptake of lutein and β-carotene, 2 of the 3 main carotenoids of the human diet. The aim of this work was therefore to determine whether SR-BI and NPC1L1 (Niemann-Pick C1-like 1), another cholesterol transporter, are implicated in absorption of lycopene, the 3rd main carotenoid of the human diet. Anti-human SR-BI antibody and block lipid transport 1 (BLT1) (a chemical inhibitor of lipid transport by SR-BI) impaired up to 60% (all-E) and (5Z)-lycopene uptake (P < 0.05) by Caco-2 cell monolayers, which were used as a model of human intestinal epithelium. The involvement of SR-BI in lycopene absorption in vivo was then verified by comparing plasma lycopene concentrations in wild-type and SR-BI transgenic mice that were fed a diet enriched with 0.25 g/kg (all-E)-lycopene for 1 mo. Plasma lycopene concentrations were 10-fold higher (P < 0.001) in mice overexpressing SR-BI in the intestine than in wild-type mice, confirming the involvement of SR-BI in lycopene absorption. Further experiments showed that (all-E)-lycopene did not affect SR-BI mRNA levels in Caco-2 cells or mouse intestine. In contrast to SR-BI, neither anti-human NPC1L1 antibody nor ezetimibe, used as inhibitors of lycopene uptake via NPC1L1, significantly impaired (all-E) or (5Z)-lycopene uptake by Caco-2 monolayers. Thus, the present data show that lycopene absorption is, at least in part, mediated by SR-BI but not by NPC1L1.

	Introduction

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

	Materials and Methods

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
Chemicals

(all-E)-Lycopene (95% pure), echinenone (97% pure), placebo beadlets, and (all-E)-lycopene rich beadlets (lycopene 10% water soluble; DSM Redivivo) were a generous gift of DSM Ltd. Small amounts (several hundred micrograms) of (5Z)-lycopene were isolated using preparative C₃₀ chromatography (11). Larger amounts (5 mg) were purchased from CaroteNature. Phosphatidylcholine, lysophosphatidylcholine, monoolein, free cholesterol, oleic acid, sodium taurocholate, and pyrogallol were purchased from Sigma-Aldrich. Mouse monoclonal IgG raised against the external domain of human SR-BI was purchased from BD Transduction Laboratories. Rabbit polyclonal anti-human NPC1L1 IgG was purchased from Abcam. BLT1, a chemical inhibitor of lipid transport mediated by SR-BI, was purchased from Chembridge. Ezetimibe, a chemical inhibitor of cholesterol transport mediated by NPC1L1 (12), was purchased from Sequoia Research Products. DMEM containing 4.5 g/L glucose and trypsin-EDTA (500 mg/L and 200 mg/L, respectively) as well as RPMI 1640 medium were purchased from BioWhittaker. Fetal bovine serum was from Biomedia. Nonessential amino acids, penicillin/streptomycin, and PBS were purchased from Invitrogen. TRIzol reagent, random primers, and Moloney murine leukemia virus RT were obtained from Invitrogen. SYBR Green reaction buffer was obtained from Eurogentec. The Protease inhibitor mixture was a gift from F. Tosini (Avantage Nutrition). All solvents used were HPLC grade from Carlo Erba, SDS. Enriched nonpurified diets were prepared by the "Unité de Préparation des Aliments Expérimentaux" (INRA) by mixing either placebo beadlets or lycopene beadlets with the basic nonpurified diet at the proportion of 0.25 g lycopene/kg diet.⁹

Preparation of lycopene-rich micelles

To deliver lycopene to cells, mixed micelles were prepared as previously published (7) to obtain the following final concentrations in DMEM: 0.04 mmol/L phosphatidylcholine, 0.16 mmol/L lysophosphatidylcholine, 0.3 mmol/L monoolein, 0.1 mmol/L free cholesterol, 0.5 mmol/L oleic acid, 0.2–0.6 µmol/L (all-E) or (5Z)-lycopene (13,14), and 5 mmol/L taurocholate. The concentration of lycopene in the micellar solutions was checked by HPLC before each experiment.

Cell culture

Caco-2, clone TC-7 cells (15,16), were a gift from Dr. M. Rousset (INSERM U178). Cells were cultured in the presence of DMEM supplemented with 20% heat-inactivated fetal bovine serum, 1% nonessential amino acid, and 1% antibiotics (complete medium) as previously described (7).

Lycopene uptake measurement

For uptake experiments, cells were seeded at a density of 10,000 cells/cm² in 6-well plastic dishes (BD Falcon) and the medium was renewed every 2 d. On d 14 postseeding, at the beginning of each experiment, cell monolayers were washed twice with 0.5 mL PBS. Then cell monolayers received the lycopene-rich micelles (1 mL, 40 ng of lycopene/well) for 1 h at 37°C. At the end of each experiment, media were harvested. Cells were then washed twice with 0.5 mL ice-cold PBS containing 10 mmol/L taurocholate to eliminate adsorbed lycopene, scraped, and collected in 0.5 mL PBS. Uptake of lycopene was estimated as lycopene found in scraped cells. All the samples were stored at –80°C under nitrogen with 0.5% pyrogallol to prevent oxidation during lycopene extraction and HPLC analysis. Aliquots of cell samples without pyrogallol and containing protease inhibitors were used to estimate protein concentrations with a bicinchroninic acid kit (Pierce).

Involvement of SR-BI in lycopene uptake by Caco-2 cell monolayers

    Effect of anti-human SR-BI antibody on lycopene uptake. Differentiated cells were incubated for 10 min with 3.75 mg/L anti-human SR-BI monoclonal antibody raised against the external domain before lycopene-rich micelles were added for 60 min and lycopene uptake was measured as described above. Dose-response experiments performed in our laboratory have shown that this antibody concentration allows a maximal inhibition of absorption of lutein, a carotenoid absorbed, at least partly, via SR-BI (7). Anti-human SR-BI antibody raised against the C-terminal domain was used as a negative control at 3.75 mg/L (7,17).

    Effect of BLT1 on lycopene uptake. BLT1 is a chemical inhibitor of SR-BI. Differentiated cells were pretreated with either dimethyl sulfoxide (control) or BLT1 solubilized in dimethylsulfoxide at 10 µmol/L for 1 h (7). Dose-response experiments performed in our laboratory have shown that this concentration allows a maximal inhibition of absorption of lutein without cytotoxicity. Then, cells received lycopene-rich micelles with BLT1 at the preincubation concentration for 60 min (18). At the end of incubation, cells were scraped and absorbed lycopene was measured as previously described.

Lycopene bioavailability in wild-type mice and in mice overexpressing SR-BI in the intestine

Three- to 6-mo-old male mice (6 wild-type and 6 transgenic mice) with a C57/Bl6 background were used for the study. They were delivered by Dr. Xavier Collet (INSERM). Transgenic mice overexpressing SR-BI in the intestine were described previously (19). SR-BI overexpression in the intestine was confirmed by RNA quantification as well as by immunocytochemistry. The mice were housed in a temperature-, humidity-, and light-controlled room. They were fed 6 g/d of a lycopene-enriched nonpurified diet (SAFE, AUGY) (0.25 g of lycopene/kg diet) and consumed water ad libitum for 30 d. Mice were deprived of food overnight before the experiment. On the day of the experiment, blood samples were obtained by retro-orbital sampling under anesthesia. Plasma was isolated and stored at –80°C until lycopene analysis. Animal studies on fat-soluble micronutrient metabolism were approved by the local ethic committee (Commission d'éthique Animale de la Faculté de Médecine de Marseille).

Involvement of NPC1L1 in lycopene uptake by Caco-2 cell monolayers

    Effect of anti-human NPC1L1 antibody on lycopene uptake. Differentiated cells were incubated for 10 min with 6 mg/L of anti-human NPC1L1 antibody (20) before (all-E) or (5Z)-lycopene–rich micelles were added for 60 min. Haikal et al. (20) have shown that this antibody used in the same conditions is able to impair cholesterol absorption significantly.

    Effect of ezetimibe on lycopene uptake. Ezetimibe is assumed to impair cholesterol absorption by an inhibitory effect on NPC1L1. Inhibition has been reported to occur in the concentration range of 10–150 µmol/L in cultured cells (21). Differentiated cells were pretreated with either ethanol (0.1%) as a control or an ethanolic solution of ezetimibe at 150 µmol/L for 60 min. Cells then received (all-E) or (5Z)-lycopene–rich micelles with ezetimibe at the preincubation concentration for 60 min (21).

Effect of lycopene on mRNA levels of SR-BI and NPC1L1

    In Caco2-TC7 cells. Caco-2 cells were plated on 6-well plates and incubated for 18 h with either placebo beadlets or beadlets rich in (all-E)-lycopene solubilized in the aqueous medium to provide 10 µmol/L of lycopene per well. We chose this concentration because it has been shown that lycopene concentration in the human duodenal lumen can reach 10 µmol/L after a lycopene rich-meal (22) and we wanted to maximize our chance to observe an effect of lycopene on gene expression. We chose to provide lycopene in beadlets instead of micelles, as in the uptake experiments, because this vehicle: 1) allows solubilization at a higher concentration of lycopene in the medium; 2) can provide lycopene to intracellular compartments (lipid droplets and nuclear membrane of adipocytes; data not shown); and 3) does not modify the expression of several genes involved in lipid metabolism [assessed by quantitative RT-PCR (Q-RT-PCR); data not shown]. Total cellular RNA was extracted using TRIzol reagent. The cDNA was synthesized from 1 µg of total RNA in 20 µL using random primers and Moloney murine leukemia virus RT. Real-time Q-RT-PCR analyses were performed using the Mx3005P Real-time PCR system (Stratagene). For each condition, expression was quantified in duplicate and 18S mRNA was used as the endogenous control in the comparative cycle threshold method.

    In mouse intestinal segments. Duodenums were excised from killed mice that ate either a diet without lycopene or a diet that contained 0.25 g/kg (all-E)-lycopene for 1 mo. Intestinal RNA isolation and real-time Q-RT-PCR analyses were performed as described above.

Lycopene extraction and HPLC analysis

Lycopene was extracted from 500 µL of aqueous samples using the following method. Distilled water was added to sample volumes below 500 µL to reach a final volume of 500 µL. The mixture obtained after addition of 500 µL ethanol containing echinenone as an internal standard was extracted twice with 2 volumes of hexane. The hexane phases obtained after centrifugation (500 x g; 5 min, 25 ± 3°C) were pooled and evaporated completely under nitrogen. The dried extract was dissolved in 100 µL of acetonitrile/dichloromethane (50:50, v:v). A volume of 80 µL was used for HPLC analysis.

Lycopene was separated using a 250- x 4.6-nm RP C₃₀, 5-µm YMC column (Interchim), and a guard column. The mobile phase was 50% methanol, 40% methyl-tert butyl ether, and 10% ethyl acetate. The flow rate was 1 mL/min and the column was kept at 30°C. The HPLC system comprised a Dionex separation module (P680 HPLC Pump and ASI-100 Automated Sample Injector, Dionex SA) and a Dionex UVD340U photodiode array detector. (all-E) and (5Z)-lycopene, as well as echinenone, were identified by retention time and spectral analysis. Lycopene isomers were quantified at 470 nm and echinenone at 450 nm. Quantification was performed using Chromeleon software (version 6.50 SP4 Build 1000, Dionex). The limit of quantification was 500 pg lycopene. The recovery yield was higher than 70%.

For mouse plasma, which contained very low levels of lycopene (see Fig. 2), a specific HPLC method was developed on an Agilent model 1100 series HPLC system. This method allowed for quantification of 20 pg lycopene. The column, the flow rate, and the temperature were the same as described above, but the mobile phase was 65% methyl-tert butyl ether, 33% methanol, and 2% ammonium acetate buffer (1 mol/L, pH 4.6). An ESA Model 5600 Coularray electrochemical detector equipped with 4 channels in series was used for analysis. The potential settings used were 200–500 mV in 100-mV increments. The chromatographic data were collected and integrated using the ESA Coularray software and data management system.

View larger version (9K): [in this window] [in a new window]   FIGURE 2  Plasma lycopene concentrations in wild-type mice (control, n = 6) and in those overexpressing SR-BI in the intestine (Tg SR-BI, n = 5) fed a lycopene-rich diet (0.25 g/kg) for 1 mo. Values are means ± SD. **Different from control, P < 0.01.

Results are expressed as means ± SD. Differences between 2 groups of unpaired data were tested by the nonparametric Mann-Whitney U test. Values of P < 0.05 were considered significant. All statistical analyses were performed using Statview software version 5.0 (SAS Institute).

	Results

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
    Effect of SR-BI inhibitors on lycopene uptake by Caco-2 monolayers. In the first set of experiments, we assessed whether SR-BI was involved in lycopene uptake by using Caco-2 cells and SR-BI inhibitors (a blocking antibody and a specific chemical inhibitor). We first verified the efficiency of these inhibitors by using positive and negative controls. Concerning the positive control, recent experiments performed by another team (15) in our laboratory using the same conditions (Caco-2 and the same antibody) have confirmed the implication of SR-BI in intestinal uptake of cholesterol. Concerning the negative control, we have found no inhibition of retinyl palmitate (preformed vitamin A) uptake by caco-2 cells by adding the same inhibitors (data not shown), showing that some fat-soluble micronutrients are not absorbed via the SR-BI. The addition of anti-human SR-BI antibody raised against the C-terminal domain of SR-BI, i.e. the negative control, did not significantly affect lycopene uptake (data not shown). Conversely, the anti-human SR-BI antibody raised against the external domain of SR-BI, i.e. the blocking antibody, as well as the chemical inhibitor of SR-BI (BLT1) decreased (P < 0.05) lycopene uptake (Fig. 1). The percentage of (all-E)-lycopene uptake varied from 3% without inhibitors to 1.2% after the treatment with BLT1. (5Z)-Lycopene uptake ranged from 5% without inhibitors to 2.5% after addition of inhibitors.

View larger version (8K): [in this window] [in a new window]   FIGURE 1  Effect of anti-human SR-BI antibody and BLT1 on (all-E) and (5Z)-Lycopene uptake by Caco-2 TC7 monolayers. Values are means ± SD, n = 3 independent experiments. *Different from the control (assay performed with control antibody and without BLT1), P < 0.05.

    Effect of NPC1L1 inhibitors on lycopene uptake by Caco-2 monolayers. Because inhibitors of SR-BI did not fully impair lycopene uptake (Fig. 1), we decided to assess whether another candidate transporter, the NPC1L1, was involved in this phenomenon. The same research strategy was applied with the use of specific inhibitors of NPC1L1. The anti-NPC1L1 antibody, which significantly impaired cholesterol uptake by Caco-2 cells under the same conditions (20), did not affect either (all-E) or (5Z)-lycopene uptake by our cell monolayers (data not shown). Similarly, ezetimibe, the chemical inhibitor of NPC1L1, did not affect lycopene uptake (data not shown).

    Effect of lycopene on intracellular levels of SR-BI and NPC1L1 mRNA in Caco-2 and in mouse intestine. Because molecules can modulate their uptake by and efflux from cells via a direct effect or by an effect of their metabolite(s) on membrane proteins involved in the processes, we assessed the effect of lycopene on mRNA levels of the 2 candidate transporters in Caco-2 cells as well as in mouse intestine. Real-time RT-PCR measurements of SR-BI and NPC1L1 mRNA showed that incubation of Caco-2 with (all-E)-lycopene and dietary intake of lycopene by mice did not affect either mRNA expression (data not shown).

	Discussion

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
The involvement of the candidate transporters SR-BI and NPC1L1 in lycopene uptake by the apical side of the enterocyte was first studied using Caco-2 TC-7 cell monolayers as a model of human intestinal epithelium. Caco-2 cells spontaneously differentiate into polarized absorptive cell monolayers and display morphological and biochemical characteristics similar to human enterocytes after differentiation. This model gives reproducible values that closely correlate with in vivo data and has been used to study the molecular mechanisms involved in absorption of cholesterol (15), vitamin E (24), and carotenoids (7).

The first noteworthy observation was that (all-E) and (5Z)-lycopene uptake by the cell monolayers was impaired by both the anti-human SR-BI antibody and BLT1. These results are the first argument for the involvement of SR-BI in lycopene uptake. To further this theory on the involvement of SR-BI in lycopene absorption, we compared lycopene bioavailability between wild-type mice and mice overexpressing SR-BI in the intestine. The fact that, after 30 d of lycopene supplementation, plasma lycopene concentrations were significantly higher in transgenic mice than in control mice provides good evidence that SR-BI is involved in intestinal absorption of lycopene. The involvement of this membrane transporter is not surprising, because SR-BI seems to have low substrate specificity, mediating the transport of many lipophilic substances (6,7,24–26).

In a 2nd step, we studied the implication of another candidate transporter, NPC1L1 (9). To estimate the role of this transporter in lycopene uptake, we used a blocking anti-NPC1L1 antibody and ezetimibe, a chemical inhibitor of NPC1L1 (12). In our experiments, none of these inhibitors significantly impaired either (all-E) or (5Z)-lycopene uptake, whereas cholesterol uptake was impaired (10,25). This result is in agreement with a recent study that showed, using a small interfering RNA strategy, the lack of involvement of NPC1L1 in uptake of provitamin A carotenoids by Caco-2 cell monolayers (26).

Because NPC1L1 has a sterol-sensing domain, it is tempting to speculate that it is more selective than SR-BI and it acts as a detector (27,28). Another explanation for the noninvolvement of NPC1L1 in lycopene uptake may be its localization, because it is possibly an intracellular membrane protein involved in cytosolic trafficking of cholesterol (29,30).

The fact that the tested SR-BI inhibitors did not fully impair lycopene uptake, together with the fact that NPC1L1 is not involved in lycopene uptake, suggests that another mechanism is involved in the absorption of this carotenoid. This mechanism may involve either a passive diffusion mechanism or another apical membrane transporter. Cluster determinant 36 would be a good candidate, because it has been involved in β-carotene uptake by enterocyte (31). Because the cellular uptake of numerous molecules is regulated by the molecules themselves or their metabolites via modulation of expression of membrane transporters involved in their uptake/efflux, we examined whether lycopene can modulate SR-BI mRNA levels, as has been shown for sterols (28,32). Nevertheless, (all-E)-lycopene apparently does not affect SR-BI mRNA levels, suggesting that it does not modulate the efficiency of its absorption via effects on the expression level of this transporter.

In summary, the data presented here show that the 2 main isomers of lycopene present in tomato products are taken up by the apical membrane of the enterocyte via a facilitated process that involves SR-BI but not NPC1L1. They also suggest that lycopene is not able to regulate its own absorption via a regulation of SR-BI expression. Finally, the results suggest that another transporter or passive diffusion also may be involved in lycopene uptake by enterocytes.

	ACKNOWLEDGMENTS

 
The authors thank C. Thabuis, M. André, and M. Steib for valuable help and technical assistance.

	FOOTNOTES

 
¹ Supported by the European Community's Sixth Framework Programme. The funding was attributed to the LYCOCARD project (no. 016213), which is an integrated project within the framework of the "Food Quality and Safety" programme. This publication reflects only the authors' view. The LYCOCARD community is not liable for any use that may be made of the results.

² Author disclosures: M. Moussa, J.-F. Landrier, E. Reboul, O. Ghiringhelli, C. Coméra, X. Collet, K. Fröhlich, V. Böhm, and P. Borel, no conflicts of interest.

⁸ Abbreviations used: BLT1, block lipid transport 1; NPC1L1, Niemann-Pick C1-like 1; Q-RT-PCR, quantitative RT-PCR; SR-BI, scavenger receptor class B type I.

⁹ Nonpurified diet composition (g/kg): protein, 157; fat, 28; ash, 56; fiber, 43.

Manuscript received 8 April 2008. Initial review completed 27 April 2008. Revision accepted 29 May 2008.

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