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Biochemical and Molecular Actions of Nutrients

Uptake of Micellar Long-Chain Fatty Acid and sn-2-Monoacylglycerol into Human Intestinal Caco-2 Cells Exhibits Characteristics of Protein-Mediated Transport¹

Department of Nutritional Sciences, Cook College, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901

³To whom correspondence should be addressed. E-mail: storch{at}aesop.rutgers.edu.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Long-chain fatty acid and sn-2-monoacylglycerol (2-MG) are the digestive products of dietary triacylglycerol (TG) hydrolysis. Although fatty acid uptake into the enterocyte has been examined widely, less is known about 2-MG uptake, and few studies have mimicked the physiologic conditions present in the postprandial situation. In this study, the cellular uptake of oleic acid and 2-monoolein, presented in taurocholate micellar solution, was examined in human intestinal Caco-2 cells to model the postprandial intestinal milieu. Initial uptake of oleic acid and 2-MG displayed a saturable function of their monomer concentrations, suggesting that fatty acid and 2-MG uptake may be protein-mediated processes at low unbound concentrations of lipid. The initial rate of oleate uptake was faster and the apparent K_m was lower than values for 2-MG. Unlabeled oleic acid and, to a lesser extent, unlabeled 2-MG, inhibited the uptakes of both [³H]oleic acid and [³H]2-monoolein, suggesting competitive uptake. The nonphysiologic isomer sn-1-MG had effects similar to 2-MG, whereas the intermediate digestive product, diacylglycerol (DG), did not inhibit either oleate or 2-monoolein uptake. These results suggest that in the postprandial state, fatty acid and 2-MG derived from dietary TG are transported into the enterocyte, at least in part, via a protein-mediated pathway that is shared by both lipids, but not by the intermediate digestive product, DG.

KEY WORDS: • sn-2-MG • fatty acid • taurocholate • postprandial • Caco-2 cells

The majority of dietary lipid is triacylglycerol (TG)⁴ containing long-chain fatty acids. TG is hydrolyzed primarily by pancreatic lipase in the lumen of the proximal small intestine to produce 2 fatty acids and an sn-2-monoacylglycerol (2-MG). These lipid products are found solubilized in larger aggregates, namely, bile salt mixed micelles and unilamellar vesicles (1). In the normal situation, the micellar phase predominates (2). We showed previously that lipid transport rates from micelles were far more rapid than rates from vesicular phases (3). Thus, the bile salt micelle is the primary lipid milieu from which fatty acid and 2-MG uptake into the absorptive enterocyte occurs. Although the mechanism of fatty acid uptake into cells has been studied extensively (4–7), there are only a few reports that examined cellular 2-MG uptake (8–10).

Studies of lipid uptake in cell culture have typically used lipids solubilized with serum albumin because albumin is the major carrier of lipids in plasma, and binding affinity values are available (11,12). The kinetic analysis of uptake is carried out by monitoring the initial rates of uptake as a function of ligand concentration. Because lipid aggregates such as micelles are not incorporated into cells as intact species (13,14), the monomer concentration, free from the aggregate, is considered the actual ligand. Thus, although bovine serum albumin (BSA) solutions are useful for controlling the lipid monomer concentrations for kinetics studies (12,15,16), such solutions are clearly not an appropriate model of lipid presentation to the enterocyte during intestinal lipid uptake.

In a previous study, the cellular uptake of fatty acid and 2-MG was examined in Caco-2 cells (8). The initial rate of uptake of 2-MG across the apical plasma membrane was found to be a saturable function of the monomer concentration, similar to long-chain fatty acid uptake, in both micellar and BSA solutions. Competitive uptake between fatty acid and 2-MG was observed; however, the experiments were performed using BSA-bound ligand.

The purpose of this study was to examine intestinal diet-derived lipid uptake under conditions that represent the postprandial situation. Thus, lipid digestive products were solubilized in taurocholate micellar solutions, and uptake into well-differentiated Caco-2 monolayers grown on permeable filters was examined.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Materials. Tritium-labeled oleic acid and triolein were purchased from NEN. Tritiated sn-2-monoolein was obtained from [³H]triolein by digestion with pancreatic lipase, as previously described (8) and stored at –20°C in hexane. Tritium-labeled sn-1-monoolein was obtained with sn-2-monoolein, as a minor product following pancreatic lipase digestion. Unlabeled oleic acid was purchased from Nu-Chek-Prep. Unlabeled 2-monoolein, 1-monoolein, and diolein were from Serdary Research Lab. BSA (fatty acid free), Triton X-100, and pancreatic lipase (type VI) were purchased from Sigma Chemical. Sodium taurocholate (TC) was from Calbiochem. Cell culture media and reagents were obtained from GIBCO.

    Cell culture. Caco-2 cells were grown as described previously (4,8). For experiments, cells were plated at a density of 3 x 10⁵ cells/cm² onto polycarbonate Transwell filter inserts with 0.4-µm pores (Costar), and were grown to 14–22 d postconfluence. Cells at passage 40–56 were used.

    Preparation of taurocholate-mixed micellar solution. Radiolabeled oleic acid, 2-MG, or 1-MG was dried under N₂. The dried lipids were dissolved in 0.5% (v:v) of ethanol relative to final volume, dispersed in 10 mmol/L TC in PBS, pH 7.4, to obtain the desired concentration, and were further incubated for 1 h at 37°C with shaking at 90 rpm to obtain a homogenous solution. The specific activities of the uptake solutions were 1–20 µCi/nmol for each ligand. For competition studies, unlabeled lipids were mixed with a radiolabeled ligand to obtain the desired ratio. All solutions were used at 37°C for uptake studies.

    Determination of unbound lipid concentrations in taurocholate micellar solutions. The monomer concentrations of lipids were determined by the ultrafiltration method described previously (8).

    Lipid uptake assay. The initial rates of uptake of the TC-mixed lipids were determined similarly to our previous studies (8). Initial rates of uptake were determined over a range of ligand concentrations to obtain the apparent Michaelis-Menten constant (K_m) and maximum velocity (V_max) of uptake using the nonlinear regression analysis by Prism 4 (GraphPad Software) and Woolf plots, as previously described (4). The data were fit to both a saturable (Michaelis-Menten) function and to a combined saturable plus linear function. At low total substrate concentrations, i.e., <200 µmol/L oleic acid and <125 µmol/L 2-MG, which reflected the stable monomer concentrations (Fig. 1), the combination did not improve the fit. Thus, uptakes were analyzed by fitting the data for unbound concentrations of 3.2 µmol/L oleate and 6.5 µmol/L 2-MG, to the Michaelis-Menten equation. For competition studies, unlabeled oleic acid, 2-MG, 1-MG, and DG were added to radiolabeled oleic acid or 2-MG, and uptake assays were performed as described above. For competitive uptake studies, the total concentration of the lipid was always below its corresponding highest concentration in the linear range [e.g., its critical micellar concentration (CMC)].

View larger version (14K): [in this window] [in a new window]   FIGURE 1 Monomer concentrations of oleic acid and 2-monoolein in 10 mmol/L TC micellar solution. TC-mixed radiolabeled lipid was filtered, and the radioactivity in the filtrate were estimated as the monomer fraction. Results are means ± SD, n = 3. When no error bars appear, the SD values were smaller than the symbols.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Monomer concentrations of oleic acid and 2-MG in micellar solution. The unbound monomeric concentrations of lipids were estimated by filtration, as described above. Unbound oleic acid in a 10 mmol/L TC micellar solution was consistently 1.6% of the total concentration, up to 250 µmol/L (4.0 µmol/L as the monomer) (Fig. 1). At higher oleic acid concentrations, the proportion of the monomer became lower and unstable. The monomer concentration of 2-MG was 5.0% when the total 2-MG concentration was <125 µmol/L (6.25 µmol/L as the monomer) (Fig. 1). Higher concentration solutions showed lower and unstable unbound levels, similar to oleate. In the case of 1-MG, the proportion of monomer was 3.0% of its total concentration up to 250 µmol/L (data not shown).

The highest monomer concentrations observed within the linear range were similar to the reported CMC values of 6.0 µmol/L for oleic acid (17) and 4.2 µmol/L for 2-MG (8).

    Rates of uptake of oleic acid, 2-MG, and 1-MG from micellar solution. The kinetic parameters of uptake were determined using the 10-s point for various concentrations of lipids because the apical uptake of TC-mixed lipids was a linear function of time within 20 s and because metabolism of the lipids was minimal, as previously reported (8). The monomer concentration of the incubation medium did not change after a 10-s incubation with cells (data not shown). Uptake rates were plotted as a function of unbound monomer concentration of lipid (Fig. 2A). At lower concentrations of unbound ligands, the apical uptake of TC-mixed oleic acid and 2-MG appeared to be a saturable function of the monomer lipid concentration, suggesting that facilitated transport was occurring for both 2-MG and long-chain fatty acid. At higher concentrations, the lipid uptake showed a linear function of the mean concentration of its ligand (Fig. 2A).

View larger version (18K): [in this window] [in a new window]   FIGURE 2 (A) Initial rates of apical TC-mixed lipid uptake into Caco-2 cells. Caco-2 cells were incubated with TC-mixed radiolabeled lipid (oleic acid, 2-monoolein, or 1-monoolein) for 10 s, and the intracellular radioactivity was measured. Dashed lines show the Michaelis-Menten fits for oleic acid and 2-monoolein. The uptake data for concentrations 3.2 µmol/L of unbound oleate and 6.5 µmol/L of unbound 2-MG were fit to the Michaelis-Menten equation. Results are means ± SD, n = 5. (B) Woolf plots of oleic acid and 2-monoolein uptake into Caco-2 cells. [s] is the substance concentration (unbound lipid concentration) and V is the initial uptake velocity [pmol/(mg protein · 10 s)]; –Km is the intercept on the x axis, and the slope is 1/Vmax. Data are from the mean of the uptake curves evaluated in Fig. 2A.

    Influence of coexisting lipolytic products on lipid uptake from the micellar solution. To model intestinal fatty acid and 2-MG uptake under postprandial conditions, uptake was measured in the presence of other lipids that likely coexist in the micelle during dietary lipid digestion. Radiolabeled oleic acid uptake was significantly inhibited by unlabeled oleic acid (Fig. 3A). Inhibition was also observed when 2-MG was added, although the effect was weaker than that of oleic acid. The inhibitory effect of oleic acid addition (52.6 ± 9.4% of control) was significantly stronger than that of 2-MG (78.4 ± 5.4% of control) when their concentrations were 100 times higher than radioactive oleate concentration (P < 0.05). Addition of 1-MG inhibited oleate uptake to a similar extent as 2-MG, whereas DG, an intermediate product of TG digestion, did not have an inhibitory effect.

View larger version (38K): [in this window] [in a new window]   FIGURE 3 Competitive uptake of lipids in Caco-2 cells. Uptake solutions were prepared by adding excess unlabeled lipids to radiolabeled TC-mixed lipids and incubated with Caco-2 cells for 10 s. (A) 0.02 µmol/L of monomer [3H]oleic acid uptake with unlabeled oleic acid, 2-MG,1-MG, and DG. (B) 0.03 µmol/L of [3H]2-MG uptake with unlabeled oleic acid, 2-MG, 1-MG, and DG. Unlabeled oleate and MGs were added in the desired ratio of monomer concentration to corresponding radiolabeled lipid. DG was added as 100 µmol/L of the total concentration. Data are means ± SD, n = 6. Letters indicate different from corresponding lipid uptake without cold competitor, aP < 0.01; bP < 0.05.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
In this study, uptake rates of the major products of dietary lipid digestion, solubilized in a micellar solution, were investigated using human intestinal Caco-2 cells as a model of the absorptive enterocyte under postprandial conditions. As Hernell et al. (1) demonstrated, the triacylglycerol digestive products, fatty acids and MG, are present not only in a micellar phase but also in other lipid phases, particularly vesicles, in the duodenum. We showed that in vitro, the fatty acid and monocylglycerol transfer rates in micelles are markedly faster than those in unilamellar vesicles; thus, micelles are likely to deliver the majority of the lipid digestive products to the enterocyte (3). Moreover, under normal digestive conditions, the lipids are expected to be present mainly in the micellar phase, due to high luminal bile salt concentrations. Thus, the initial rates of lipid uptake in vivo likely reflect rapid lipid transfer between micelles and the enterocyte membrane, the process assessed in the present experiments. To estimate the kinetic parameters of oleic acid and 2-MG uptake, monomer concentrations in 10 mmol/L TC micellar solutions were evaluated by ultrafiltration because it is widely believed that lipid uptake occurs from the soluble monomeric phase (13,14). The unbound concentration of oleic acid in 10 mmol/L TC solution was similar to that reported for other fatty acids (5,6). The concentration of the 2-MG monomer was higher. The constant ratio between the monomer and its total concentration was not observed at higher lipid concentrations, likely due to their exceeding the CMC.

In a previous study, we reported that the V_max values of micellar fatty acid and 2-MG uptake were considerably higher than those of BSA-bound lipid uptake, whereas the K_m values of micellar lipid were lower than those of BSA-bound lipid (8). The K_m values here were higher because the monomeric concentrations of lipid in 10 mmol/L TC micelle had been underestimated previously. Thus, the lipid micelles used in our previous study (8) were of higher total concentration, and the stability of the monomer concentration in the micelle was lower than that in the range of concentrations used in this study. This resulted in a clearly saturated uptake profile because the CMC had likely been exceeded; in the reliable range of concentrations (containing stable monomer concentrations) used herein, the uptake of oleic acid and 2-MG also showed saturable functions of unbound concentrations, although the saturation was not as dramatic. The reestimated micellar V_max values are still considerably higher than the V_max values obtained from BSA-bound lipid uptake, in agreement with others (18,19).

Oleic acid and 2-MG uptake showed a saturable function of their unbound concentrations, supporting the suggestion that dietary lipid uptake into the enterocyte may occur in part by a protein-mediated pathway. The K_m of oleic acid was lower than that of 2-MG, indicating that oleic acid is a more favorable ligand for a putative transmembrane transport protein. In a model system study, it was found that the transfer rate of fatty acid from micellar solutions was faster than that of 2-MG (3). Thus, the delivery of fatty acid for enterocyte uptake may be more rapid than for 2-MG, which could in part underlie the more favorable uptake of fatty acid found here. When higher total concentrations of lipids were incubated with Caco-2, there was a linear relation between the uptake and the apparent monomer concentration (Fig. 2A), suggesting that a passive diffusion mechanism coexists with the carrier-mediated pathway when the total TG lipid concentration is high, as suggested previously (8). Such a dual mechanism of micellar fatty acid uptake was also reported by Chow and Hollander (20) for linoleic acid uptake by rat everted gut sacs, although the boundary concentration between facilitated and passive diffusional uptake was somewhat higher than our concentration (Fig. 2), possibly due to differences in fatty acid species and/or the micelle preparation method.

When dietary TG is digested in the small intestine, the digestive products are subsequently incorporated into bile salt micelles, thereby increasing water solubility. The micelle can approach the enterocyte apical surface through the unstirred water layer, which may play an important role in increasing the concentration of fatty acid and 2-MG at the cell surface. In this study, competition between FA and 2-MG uptake was found in the micellar solution. Similar competitive effects were found with BSA-bound lipids (8), although the degree of inhibition was greater than that observed here. Relatively low competitive effects were also found when fatty acid and other inhibitors, such as FAME, were solubilized together in a micelle (5,7). In our previous model system study, we found that intermicellar lipid transfer occurred more rapidly and through a collision-mediated mechanism at high micellar levels in contrast to slower aqueous diffusional transfer at low micelle concentrations (3). In BSA solutions, lipid transfer from BSA to cells is thought to be diffusional under all circumstances; it is possible that the presence of micelle-plasma membrane collisional interactions may lead to decreased competitive uptake between ligands.

DG, the intermediate product of TG hydrolysis, did not have any inhibitory effect on FA or 2-MG uptake. In a previous report using rat intestinal IEC-6 cells (21), DG also had no inhibitory effect on fatty acid uptake. On the other hand, 1-MG and 2-MG behaved similarly (Fig. 3). Although the product of pancreatic lipase action is predominantly the sn-2-MG isomer, it is unstable and easily isomerized to sn-1-MG under various conditions (22). Some isomerization of radiolabeled 2-MG was also observed while preparing the uptake solutions in this study (6%, data not shown). This suggests that a fatty acid would compete with its counterpart of TG hydrolysis even after the isomerization occurred, although 2-MG uptake is likely to occur quickly. In contrast to the similar result found here for the 2 MG isomers, 1-MG was reported to have less of an inhibitory effect on fatty acid uptake than 2-MG in IEC-6 cells (21). The widely used Caco-2 line is derived from human colon cancer cells and, as detailed previously (4), it possesses several features relevant to enterocyte lipid metabolism (23). The IEC-6 line is another model used to study lipid metabolism in the enterocyte; these are derived from immature rat intestinal epithelial cells (24). It is not clear whether either cell model is ideal for examining the transmembrane transport of fatty acid and MG in the enterocyte. Two candidate fatty acid carriers in the small intestine, plasma membrane fatty acid-binding protein (FABPpm) (25,26) and fatty-acid transport protein 4 (FATP4) (27), were found to be expressed in Caco-2 cells (4,8), but CD36/FAT was not (28). In contrast, IEC-6 cells were reported to express CD36 and FATP4 (7). It is possible, therefore, that the difference in CD36 expression in these 2 cell lines could underlie the differential inhibitory effects of 1-MG found in the IEC-6 cells. Studies with the CD36 null mouse showed that CD36 plays a more important role in heart, muscle, and adipose tissues (29) and may be less important in the intestine (30). Thus, it is possible that Caco-2 cells could be the better model for studies of transmembrane intestinal lipid absorption. Nevertheless, this raises the important general issue of cell culture models. In attempting to dissect the kinetic and molecular events that describe fatty acid and MG transport to and into the enterocyte, such simple systems afford the ability to isolate single steps in appropriate time scales, but nevertheless must always be viewed as having limitations in direct comparison with the native intestine. Ultimately, we wish to integrate the findings in cell culture models with other experimental systems, particularly in vivo whole-animal studies.

In summary, fatty acid and 2-MG in TC micellar solution showed saturable and competitive uptake into Caco-2 cells. DG, the intermediate digestive product, did not inhibit the uptake of either fatty acid or 2-MG, whereas 1-MG, a structural isomer of 2-MG, had properties similar to 2-MG. These results suggest that under postprandial physiologic conditions, diet-derived fatty acid and 2-MG may be transported into the enterocyte, at least in part, via a common facilitated protein-mediated pathway.

	FOOTNOTES

 
¹ Supported by Public Health Service, National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-38389 (J.S.), and by state funds.

² Present address: Department of Food Science, Graduate School of Nutrition and Biosciences, The University of Tokushima, Tokushima 770-8503, Japan.

⁴ Abbreviations used: BSA, bovine serum albumin; CMC, critical micellar concentration; DG, diacylglycerol; FATP4, fatty-acid transport protein 4; MG, monoacylglycerol; TC, sodium taurocholate; TG, triacylglycerol.

Manuscript received 11 November 2004. Initial review completed 30 December 2004. Revision accepted 18 March 2005.

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TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

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