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Journal of Lipid Research, Vol. 44, 533-538, March 2003
Copyright © 2003 by Lipid Research, Inc.

Comparison of the intestinal uptake of cholesterol, plant sterols, and stanols in mice

Michael Igel, Uwe Giesa, Dieter Lütjohann and Klaus von Bergmann¹

Department of Clinical Pharmacology, University of Bonn, Germany

Published, JLR Papers in Press, December 16, 2002. DOI 10.1194/jlr.M200393-JLR200

¹ To whom correspondence should be addressed. e-mail: vonbergmann{at}uni-bonn.de

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The recent identification of the aberrant transport proteins ABCG5 and ABCG8 resulting in sitosterolemia suggests that intestinal uptake of cholesterol is an unselective process, and that discrimination between cholesterol and plant sterols takes place at the level of sterol efflux from the enterocyte. Although plant sterols are structurally very similar to cholesterol, differing only in their side chain length, they are absorbed from the intestine to a markedly lower extent. In order to further evaluate the process of discrimination, three different sterols (cholesterol, campesterol, sitosterol) and their corresponding 5-stanols (cholestanol, campestanol, sitostanol) were compared concerning their concentration in the proximal small intestine, in serum, and in bile after a single oral dose of deuterated compounds.

The data obtained support the hypothesis that i) the uptake of sterols and stanols is an extremely rapid process, ii) discrimination probably takes place on the level of reverse transport back into the gut lumen, iii) plant stanols are taken up, but not absorbed to a measurable extent, and iv) the process of discrimination probably also exists at the level of biliary excretion. The range of structural alterations that decrease intestinal absorption and increase biliary excretion is: 1) campesterol, 2) cholestanol-sitosterol, and 3) campestanol-sitostanol.

Supplementary key words phytosterols • phytostanols • stable isotope • gas chromatography-mass spectrometry • ABC-transporters

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Investigators have been intrigued for more than a decade with the concept that there is a protein-mediated transport system responsible for intestinal uptake of cholesterol (1). The recent identification of the molecular defects underlying phytosterolemia (2, 3) and the lines of evidence supporting the existence of a specific transport protein located in the brush border membrane that possibly mediates intestinal sterol absorption (4–6) has shed new light on the cellular transport of cholesterol and plant sterols. Based on the characterization of sterol uptake in brush border membranes, it is currently hypothesized that the process of intestinal sterol uptake is protein mediated and that the pumping of sterols from the intestine into the enterocyte is unselective. In phytosterolemia, a rare autosomal recessive disorder caused by mutations in the tandem ABC genes, either ABCG5 or ABCG8, affected individuals hyperabsorb and retain not only cholesterol but also plant sterols (7–11). Consequently, it is hypothesized that the ABC transporters G5 and G8 are able to discriminate between cholesterol and other sterols. They are pumping the noncholesterol sterols out of the intestinal cell back into the gut lumen and also into bile, and they are differentiating between the side-chain length and probably also between the stereoselective 5 saturation of the 5 double bond to stanols (12, 13).

Plant sterols are structurally related to cholesterol and differ in their chemical structure only due to the presence of an additional methyl (campesterol) or ethyl (sitosterol) group at the C-24 position of the side chain. Stanols differ from the corresponding sterols due to saturation of the 5 double bond to the 5 position (cholestanol, campestanol, sitostanol). Apparently, the structural differences of these sterols-stanols seem to be only of minor extent. Nevertheless, previous studies in animals and humans revealed that the efficacy of their intestinal absorption differs markedly from cholesterol (10, 14–16). However, data comparing these compounds concerning their intestinal uptake have not been experimentally verified. In order to further evaluate this hypothesis, we compared three deuterated sterols (cholesterol, campesterol, and sitosterol) and their corresponding 5-stanols (cholestanol, campestanol, and sitostanol).

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Mice
Male C57BL/6OlaHsd mice were purchased from Harlan-Winkelmann (Borchen, Germany). All experiments were carried out with four animals per group aged 8 to 11 weeks. They were fed a standard laboratory diet (1320N, Altromin, Lage, Germany), had free access to food and water, and were caged individually. Before starting the experiments, all animals were adapted to the environment and to the feeding procedure by stomach tube for 2 weeks. The Principals of Laboratory Animal Care were followed, and approval for the treatment protocol was obtained from the committee for animal care of the local administration.

Synthesis of deuterated stanols
Deuterated cholesterol, campesterol, and sitosterol were purchased from Medical Isotope, Inc. Deuterated cholestanol, campestanol, and sitostanol were synthesized by hydrogenation of the corresponding deuterated unsaturated sterols using microwaves (17).

Application of deuterated sterols and stanols
Prior to administration of deuterated sterols and stanols, mice were starved for 12 h. One single dose of 50 µl of commercially available plant oil (Livio, Union Deutsche Lebensmittelwerke, Hamburg) containing a mixture of 101 µg [²H₆]cholesterol, 82 µg [²H₅]campesterol, 109 µg [²H₅]sitosterol, 86 µg [²H₆]cholestanol, 66 µg [²H₅]campestanol, and 118 µg [²H₅]sitostanol was given by stomach tube.

Collection of serum and bile
Fifteen minutes, 30 min, 60 min, 120 min, and 240 min after the administration of deuterated sterols-stanols, mice were anaesthetized with diethylether. The chest cavity was opened and blood collected by heart puncture. Serum was obtained by centrifugation, immediately frozen in liquid nitrogen, and stored at -20°C. The gall bladder was removed. Due to the extremely small volume of bile in the gall bladder, measurement of the volume of bile was not possible. Thus, the whole gall bladder was immediately frozen in liquid nitrogen and stored at -20°C. The relations of the different sterols and stanols in bile are therefore expressed as ratios to cholesterol.

Preparation of small intestine
After the administration of deuterated sterols-stanols, the small intestine was removed at the above mentioned time points. A section of the proximal jejunum starting 3 cm distal from the Papilla Vateri and measuring 3 cm in length was prepared. The specimens were dissected, thoroughly washed in phosphate buffered saline in order to remove any intestinal content, immediately frozen in liquid nitrogen, and stored at -20°C.

Sample preparation
Before starting the extraction of lipids, the small intestine specimens were dried by vacuum, the dry weights determined, and the specimen homogenized. Lipids were extracted for 48 h in 5 ml chloroform-methanol (2:1, v/v) evaporated to dryness under a stream of dry nitrogen at 63°C, and hydrolyzed for 1 h with 1 ml of 1 M NaOH in 90% ethanol at 67°C. After the samples were cooled down to room temperature, 0.5 ml of distilled water was added. Neutral sterols were extracted twice with 3 ml cyclohexane. The combined cyclohexane phases were again evaporated to dryness under a stream of nitrogen at 63°C, and the sterols-stanols were dissolved in 100 µl n-decane. After transfer to gas chromatography (GC)-vials, the sterols were converted to trimethylsilylethers (TMSis) by adding 40 µl of TMSi reagent (pyridine-hexamethyldisilazan-trimethylchlorosilane, 9:3:1, v/v/v) and incubated at 60°C for one h.

Extraction of lipids from serum was done accordingly, except that 100 µl of serum was directly alkaline hydrolyzed with 1 ml of 1 M NaOH in 90% ethanol. Extraction of lipids from bile was performed directly in the vial containing the gall bladder by adding 1 ml chloroform-methanol (2:1, v/v).

Measurement of deuterated sterols-stanols by gas chromatography-mass spectrometry
Gas chromatography-mass spectrometry (GC-MS) was performed on a Hewlett-Packard system (5890 series II GC combined with a 5971 mass selective detector) equipped with a DB-XLB column ( J and W Scientific); 30 m; 0.25 mm ID; 0.25 µm film thickness). Samples were monitored for [²H₆]cholesterol (m/z 464), [²H₅]campesterol (main fragment M⁺⁴ m/z 476), [²H₅] sitosterol (main fragment M⁺⁴ m/z 490), [²H₆]cholestanol (m/z 466), [²H₅]campestanol (m/z 479), and [²H₅]sitostanol (m/z 493).

Calculation of deuterated sterols-stanols in small intestine
The concentrations of deuterated sterols-stanols measured in the specimen of the small intestine were corrected for the different amounts of deuterated sterol-stanol applied by stomach tube. Concentrations are expressed in ng per mg of dried intestine specimen.

Statistical methods
Data are given as mean ± SD. Probability values were calculated using Student's t-test.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The concentrations of sterols and their respective 5-stanols in the small intestine at different time points are given in Table 1. All deuterated sterols and stanols were already detectable in the intestinal mucosa 15 min after administration into the stomach. An almost uniform pattern of the concentration of sterols and stanols was seen until 240 min. In general, the concentrations of cholesterol at every time point were higher than those of campesterol, which in turn were higher than sitosterol. A similar pattern was observed with the stanols (cholestanol > campestanol > sitostanol). The concentration of cholesterol in the intestine samples increased continuously up to 7-fold during the first 120 min (Table 1). Thereafter, the concentration of cholesterol decreased markedly (P = 0.041). The concentration of campesterol was only 10% lower compared with cholesterol after 15 min (P = 0.049). After 30 min, the concentration of campesterol was twice as high compared with the concentration after 15 min, but already 39% lower than the concentration of cholesterol. The concentrations of campesterol remained constant up to 120 min and declined thereafter significantly by 53% (P = 0.015). However, the differences between the concentration of cholesterol and that of campesterol increased to 52% after 60 min and to 73% after 120 min (P = 0.001). The concentrations of sitosterol after 15 min were lower compared with the concentrations of cholesterol and campesterol. The differences at this time point were 26% and 19% lower compared with cholesterol and campesterol, respectively (P = 0.040 for both). Maximal concentrations of sitosterol were found between 30 and 60 min. The differences after 30 and 60 min to cholesterol were 62% and 72%, and to campesterol 39% and 42%, respectively. Thereafter, the concentration of sitosterol declined rapidly (by 59% and 78%) to values lower compared with any time point before (P = 0.040). The percent difference between cholesterol and campesterol as well as between campesterol and sitosterol were almost similar at every time point.

The range of the ratios of plant sterols and stanols to cholesterol in the small intestine is given in Table 2 and Fig. 1 . After 15 min, the highest ratio was that of campesterol to cholesterol (0.91 ± 0.05). This ratio declined markedly between 15 and 30 min (0.67 ± 0.14, P = 0.019), and between 60 and 120 min (P = 0.014). After 240 min, it was 0.2 ± 0.04. The ratio of sitosterol to cholesterol after 15 min (0.75 ± 0.11) was lower compared with campesterol (P = 0.022), and it declined thereafter more rapidly (Fig. 1). The difference to campesterol was significant at every later time point (P 0.009). The ratio of cholestanol to cholesterol was 0.7 ± 0.08 after 15 min. It declined in the same manner as the ratio of campesterol. A highly significant difference to the ratio of campesterol was seen after 15 min (P = 0.004), and another marked difference after 120 min (P = 0.028). The ratios of campestanol and sitostanol to cholesterol showed the most rapid decline and were almost zero after 120 min.

View larger version (18K): [in this window] [in a new window]   Fig. 1. Ratio of plant sterols and stanols to cholesterol in small intestine of mice.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

The pattern of discrimination obviously depends on the chemical structure of the sterols and stanols. This pattern could be described as follows: the addition of one methyl group at the C-24 position of the side chain (campesterol) is the smallest alteration. The saturation of the 5 double bond (cholestanol) and the addition of an ethyl group at the C-24 position (sitosterol) result in even more structural discrepancy and potency of discrimination. Alterations of both the C-24 position of the side chain and the 5 double bond (campestanol, sitostanol) leads to structural differences, which further increase the power of discrimination, especially concerning the transport into the plasma compartment.

Thirty and 60 min after their application, the process of discrimination in the small intestine between the different sterols and stanols becomes more and more obvious, and between 60 min and 120 min it is at its maximum. Thereafter, all concentrations decrease, and the ratios show no significant changes, indicating that the process of cholesterol uptake, and simultaneously the one of discrimination, are beginning to end between 120 min and 240 min. The concentrations in serum also indicate a process of discrimination between cholesterol, plant sterols, and stanols. Campestanol and sitostanol were absorbed, if at all, to such a small extent that they were not detectable in serum or bile despite high concentrations in the intestine. The range of serum concentration of sterols and cholestanol resembles the one observed in the small intestine. Between 120 min and 240 min, the concentrations of all sterols and cholestanol in serum increase, indicating that only one alteration of the chemical structure, either of the side chain or the double bond, defines the extent of absorption. Alterations of both side chain and double bond (campestanol, sitostanol) do not inhibit the uptake into the intestinal mucosa, but drastically reduce the systemic availability. A different scenario is observed in the increase of the concentration in serum and in the decrease of the ratios to cholesterol in serum. Campesterol and sitosterol show a much lower increase in their concentrations and a more rapid decrease of their ratios than cholestanol. Furthermore, the ratio of cholestanol to cholesterol in serum does not alter significantly. These data suggest that alterations of the side chain favor the elimination from serum over the saturation of the double bond. The data from bile could support the hypothesis that a process of discrimination exists between plant sterols and cholestanol on the level of clearance from serum. Plant sterols are eliminated faster and to a greater extent than cholestanol. Thus, the different alterations of the side chain would determine the rate of elimination, as indicated by the difference between the two plant sterols. On the other hand, it cannot be ruled out that the differences in bile are due to differences in uptake by the liver, although transport systems that discriminate between the different compounds concerning their uptake into liver are not described. The speculation that the discrimination also applies to sterol-stanol excretion into bile is supported by the finding that 1) ABCG5 and ABCG8 in humans are not only expressed in intestine but also in cells of the liver (3); 2) transgenic mice overexpressing human ABCG5 and ABCG8 express the transgene primarily in the liver and small intestine (18); 3) coexpreession of ABCG5 and ABCG8 results in sorting of ABCG5 to the apical, canalicular surface of hepatocytes (19); 4) overexpression of ABCG5 and ABCG8 results in biliary cholesterol concentrations more than 5-fold, and a 3- to 6-fold increase in fecal neutral sterol excretion in mice (18); 5) hepatic cholesterol levels of ABCG5/8 knock-out mice increased 18-fold on a high-cholesterol diet compared with a 3-fold increase in wild-type animals (20); 6) the fractional absorption of dietary plant sterols and cholestanol increased 2- to 3-fold in ABCG5/8 knock-out mice, although the fractional absorption of dietary cholesterol was not significantly different between the ABCG5/8 knock-out mice and wild-type animals (20); and 7) patients with sitosterolemia excrete only a small fraction of the ingested plant sterols into bile, although the concentration of plant sterols in serum and bile is markedly higher compared with unaffected individuals (2, 10).

The discrimination capacity of the small intestine between cholesterol, plant sterols, and corresponding stanols, in that cholesterol is preferentially absorbed from the intestinal lumen, is well documented in the literature (10, 15, 21–26). Only traces of campestanol and sitostanol are detectable in serum under physiological conditions (22, 26–28). In contrast, high serum concentrations of both plant sterols and stanols are present in patients with sitosterolemia (7, 9). The identification of the mutations in the tandem ABC genes, ABCG5 and ABCG8, has given credence to the hypothesis that there is a molecular pathway regulating dietary sterol and stanol absorption and biliary excretion (2, 3). Further support for this hypothesis comes from patients with Tangier disease (29–33), suggesting that even more ABC transport proteins could be involved in the regulation of sterol absorption in the intestine and from the identification of orphan nuclear hormone receptors, such as the retinoid X receptor, the liver X receptors, and the farnesoid X receptor (34) that are involved in the regulation of these transporters. These findings form the basis of the current hypothesis regarding sterol metabolism that the discrimination process does not involve the uptake from the intestinal lumen, but rather the efflux from the enterocyte back into the intestinal lumen. Consequently, the process of discrimination would require some time to build up. This hypothesis can be supported by the data obtained here, as the degree of discrimination depicted by the ratios of plant sterols and stanols to cholesterol gradually increases over time. Furthermore, the data presented here imply that the process of discrimination is an extremely rapid one that probably takes only minutes to start. Significant differences in the concentrations of cholesterol, plant sterols, and their corresponding stanols are found as early as after 15 min. Unfortunately, measurements at an earlier time point are difficult due to the design of the experiment, and probably show a much higher variability. However, in vitro data might distinguish early mechanisms of the process of discrimination.

In summary, the data show for the first time a comparison of intestinal uptake, absorption, discrimination, and biliary excretion of cholesterol, plant sterols, and the corresponding 5-stanols at short time intervals, and support the current hypothesis that the efflux rather than the uptake of sterols is the main process discriminating in favor of the absorption of cholesterol over plant sterols and stanols. Finally, the ratios of plant sterols to cholesterol in the intestine and bile at the two different time points (120 min and 240 min) indicate that the fast efflux from the intestine back into the gut lumen as well as the elimination into bile is probably regulated by the same tranporter(s). Nevertheless, further studies are needed utilizing the properties of investigational drugs and genetically altered mice, as well as in vitro experiments, to clarify this process.

	ACKNOWLEDGMENTS

 
The authors thank Anja Kerksiek and Silvia Winnen for their excellent technical assistance. This study was supported by a grant from the Bundesministerium für Bilding, Forschung, Wissenschaft und Technologie (01EC9402).

Manuscript received October 2, 2002 and in revised form December 6, 2002.

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