Food &Function

REVIEW

Cite this: DOI: 10.1039/c4fo00579a

Received 2nd July 2014,Accepted 30th September 2014

DOI: 10.1039/c4fo00579a

www.rsc.org/foodfunction

Intestinal absorption of vitamin D: from the mealto the enterocyte

Emmanuelle Reboula,b,c

Vitamin D plays key roles in bone, infectious, inflammatory and metabolic diseases. As most people get

inadequate sun exposure for sufficient vitamin D status, they need adequate intake of dietary vitamin D.

Many studies see optimizing vitamin D status as a public health priority. It is thus vital to gain deeper

insight into vitamin D intestinal absorption. It was long assumed that vitamin D intestinal absorption is a

passive process, but new data from our laboratory showed that it is actually far more complex than pre-

viously thought. This review describes the fate of vitamin D in the human upper gastrointestinal lumen

during digestion and focuses on the proteins involved in the intestinal membrane and cellular transport of

vitamin D across the enterocyte. Although recent data significantly improve our understanding of

vitamin D intestinal absorption, further studies are still needed to increase our knowledge of the

molecular mechanisms underlying this phenomenon.

Vitamin D in humans

Vitamin D was first known as an antirachitic and a regulator ofphosphate and calcium homeostasis, but recent evidenceshows that vitamin D also plays key roles in infectious, inflam-matory and metabolic diseases.1 Vitamin D3 (cholecalciferol)is produced in skin by UVB irradiation of the precursor7-dehydrocholesterol. The pre-vitamin D3 thus synthesized isthen isomerized into vitamin D3 before being released intothe blood.2 As most people get inadequate sun exposure forsufficient vitamin D status, they need adequate intake ofdietary vitamin D.3 The human diet mainly provides vitaminD3 (Fig. 1) via fish liver oil, fatty fish (sardines, herring, mack-erel), egg yolk and milk.2,4 Food supplements provide eithervitamin D3 or D2 (ergocalciferol, Fig. 1), this last form beingalso found in some mushrooms.5 Finally, the 25-hydroxy-vitamin D form of vitamin D3 is found in small amounts in awide range of animal products.6 The recommended dietaryallowance of vitamin D for healthy adults is 15 µg per day.7

This is an extremely difficult target given that few foodscontain vitamin D,8 and the NHANES study confirmed thatthe level of vitamin D in more than 75% of the US populationis insufficient.9 This alarming conclusion is global, as reportsfrom around the world indicate that hypovitaminosis D iswidespread and qualifies as a major worldwide epidemic.10 Asmany studies view optimizing vitamin D status as a publichealth priority, it is vital to gain deeper insight into vitamin Dintestinal absorption.

It was long assumed that vitamin D intestinal absorptionis a passive process,11,12 but new data from our labshowed that it is actually far more complex than previously

Emmanuelle Reboul

Dr Emmanuelle Reboul receivedan Engineering diploma in Nutri-tion and Food Sciences fromAgrosup Dijon, France in 2002.While doing her master’s degreeand PhD thesis in the “HumanNutrition and Lipids” laboratoryin Marseille, France (Dr P.Borel’s team), she studiedcarotenoid, vitamin A and Eintestinal absorption. She thenjoined the working group ofDr R.S. Molday in 2006 at theUniversity of British Columbia in

Vancouver, Canada to work on ATP transporter molecular func-tioning. Since returning to Marseille, France, in late 2008, she hasbeen working in the “Nutrition, Obesity and Risk of Thrombosis”laboratory as a researcher from the French National Institute ofAgronomical Research, where she currently focuses on fat-solublevitamin and carotenoid intestinal absorption and membranetransport.

aINRA, UMR 1260, “Nutrition, Obesity and Risk of Thrombosis”, F-13385 Marseille,

France. E-mail: Emmanuelle.Reboul@univ-amu.fr; Fax: +33 4 91 78 21 01;

Tel: +33 4 91 29 41 11bINSERM, UMR 1062, F-13385 Marseille, FrancecAix-Marseille Université, F-13385 Marseille, France

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thought.13–15 Here, we overview the fate of vitamin D in thehuman upper gastrointestinal lumen during digestion andthen focus on the putative or identified proteins involved inthe intestinal membrane and cellular transport of vitamin Dacross the enterocyte.

Fate of vitamin D during digestion

Vitamin D is thought to follow the same fate as lipids inthe upper gastrointestinal tract,16 and patients with intestinalmalabsorption, notably steatorrhea, show decreased vitaminD3 absorption.

17–19

The first step of the process of digestion is the dissolutionof vitamin D in the fat phase of the meal, which is emulsifiedinto lipid droplets in the stomach and duodenum. Only thefree forms of fat-soluble vitamins are thought to be absorbedby the intestinal cell, suggesting that esterified forms shouldbe hydrolyzed first. It was shown in rats that vitamin D3 oleate,although less absorbed than free vitamin D3, led to significantintestinal absorption and appeared in the lymph as both freeand esterified vitamin D as well as more polar product(s).20

This same study also found that vitamin D oleate was partiallyhydrolyzed by pancreatic juice, suggesting that a pancreaticlipase may be involved. A good candidate would be the choles-terol ester hydrolase,21 but other enzymes such as the pancrea-tic lipase and the pancreatic lipase-related proteins,22 orenzymes present at the brush-border membrane (BBM) level,23

may also be involved. Another study in human infants showedthat vitamin D3-palmitate and vitamin D2 were similarlyabsorbed after 10 days of age, suggesting the necessity of amature digestive tract with functional intestinal esterases.24

The fact that esterified vitamin D3 was secreted by the intes-tine20 does not necessarily mean that it was absorbed intact,as an intracellular re-esterification step may occur. However,under standard conditions, such esterification has still neverbeen clearly described.

During digestion, vitamin D is transferred from its foodmatrix to the mixed micelles generated by the lipolysis ofdietary fat.25 Mixed micelles are a mixture of phospholipids,cholesterol, lipid digestion products (such as free fatty acids,monoacylglycerols and lysophospholipids) and bile salts. It isthought that the higher the percentage of fat-soluble vitaminincorporation into micelles (a percentage called “bioaccessibil-ity”), the higher their absorption efficiency. Vitamin D3 absorp-tion was shown to be highly dependent on the presence ofbiliary salts, whereas 25-hydroxyvitamin D absorption was less

heavily affected by a lack of biliary salts.26 This bioaccessibilitydepends on a large number of factors, including the chemicalstructure of the vitamin and the nature of the other lipids con-sumed during the same meal.27 Our team found no differencebetween vitamins D3 and D2 in terms of solubility in syntheticmixed micelles: both vitamers presented a micellar incorpor-ation of 86–92% for a target concentration of 0.5 µM (personaldata). Fatty acid substitution (oleic acid vs. palmitic, linoleic,α-linolenic, arachidonic, eicosapentaenoic or docosahexaenoicacid) into synthetic mixed micelles did not influence vitaminD3 bioaccessibility either, although they did significantlymodify both micellar size and electric charge.13 Conversely,the sterol content of the mixed micelles significantly impactedvitamin D incorporation: we showed that both cholesterol andphytosterols inhibited vitamin D3 solubilization in syntheticmixed micelles in a dose-dependent manner.15

Interestingly, vitamin absorption can be improved by twocompounds able to form either micelles or host–guest com-plexes with hydrophobic compounds, i.e. tocopheryl succinatepolyethylene glycol 100028 and cyclodextrin.29

Although it is assumed that the vitamin D recovered in theaqueous fraction is localized into the mixed micelles, it mayalso be incorporated into other structures such as lipid dro-plets, vesicles (monolamellar and multilamellar liposomes),micelles or milk fat globules. Evidence comes from the obser-vation that vitamin D3 can be incorporated into phospholipidbilayers and that vesicle stability to the bile salt sodium deoxy-cholate is enhanced with vitamin D3 present.30 A fraction ofvitamin D may also be associated with proteins solubilized inthe aqueous phase. Indeed, as β-lactoglobulin – the majorwhey protein of bovine milk – is able to bind vitamin D3,

31 pro-teins originating from either diet or pancreatic/biliarysecretions could potentially bind a fraction of vitamin D andtransport it to the enterocyte.32

Vitamin D intestinal absorptionGeneral mechanisms

Studies using radiolabelled compounds indicate that theabsorption efficiency of vitamin D3 varies between 55 and 99%(mean 78%) in healthy humans. After intake of a pharmaco-logical dose, peak serum vitamin D3 concentration, which isgenerally observed at 10–12 h post-ingestion, is proportionalto the dose and returns to the baseline value within aweek.17,19,33,34

Fig. 1 Structure of the main molecules of dietary vitamin D.

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Vitamins D2 and D3 are similarly absorbed by the entero-cyte, as shown in several clinical studies.35–37 This is consistentwith the fact that Caco-2 cells showed no discriminationbetween the D2 and the D3 forms.14

The fat content of the meal does not appear to significantlymodify vitamin D absorption,38 which would suggest that italso has no effect on bioaccessibility or on uptake andsecretion by the enterocyte. However, fatty acid substitutionwithin mixed micelles containing vitamin D significantlyimpacted both vitamin D uptake and secretion by Caco-2cells.13 In particular, long-chain fatty acids decreased vitamin D3

uptake. This observation could be linked to the fact thatthe modulation of the micellar electric charge induced by thepresence of different fatty acids with different pKa

39 likelyimpacted on micelle affinity for membrane transporters (seebelow). This is consistent with an early report showing thatthe presence of long-chain fatty acids reduced vitamin D3

absorption when administered at physiological doses in rats.12

Although a clinical trial found conflicting results by showingthat the long-chain triglycerides of peanut oil allowed a betterabsorption of vitamin D than medium-chain triglycerideswhen given apart from a meal,34 another trial strengthenedthese data by showing that monounsaturated fatty acidsimproved the effectiveness of vitamin D supplementationwhereas polyunsaturated fatty acids reduced it.40 Accordingly,we have shown that oleic acid significantly improved vitaminD3 basolateral efflux compared to other fatty acids in an intes-tinal cell model in culture.13 This was partly explained by amodulation of genes coding for lipid transport proteins,13 butmay also be explained by the fact that oleic acid is importantfor an optimal chylomicron secretion in Caco-2 cells.41 Finally,we showed that on top of their effect on vitamin D incorpor-ation in mixed micelles, phytosterols also inhibited vitamin Duptake but not secretion by Caco-2 cells.15 This was in agree-ment with previous data obtained in rats supplemented withstanols for 13 weeks.42

Uptake and efflux through the brush-border membrane

Hollander’s group initially found that maximal vitamin Duptake occurs in both the jejunum and ileum,12 which is con-sistent with our recent data obtained in mice.14 The sameteam used living unanesthetized rats to conclude that vitamin Dabsorption was also passive. Indeed, vitamin D3 uptake wasincreased by H+ ions, which are believed to decrease cell mem-brane resistance to micelle diffusion, and was increased by theperfusate flow rate, which diminishes the thickness of theunstirred water layer.12 This is consistent with a clinical trialin which high doses of vitamin D were given.43 However,recent studies in our laboratory showed that three cholesteroltransporters were actually involved in this process whenvitamin D is given at dietary doses, with passive diffusionmainly able to occur at pharmacological doses.14

The first transporter identified is Scavenger Receptor ClassB type I (SR-BI, also known as CLA1 — CD36 and LIMPIIAnalogous-1 — in humans). This 80 kDa single-chain transmem-brane glycoprotein ubiquitously found within the organism44

is present at the BBM level from the duodenum to the colon.45

Initially identified as a receptor for lipoproteins,44 the SR-BIprotein is able to facilitate the selective entry into the cell com-partment of esterified cholesterol from HDL.46 At the intestinallevel, SR-BI was first shown to facilitate the uptake offree cholesterol but also esterified cholesterol, phospholipidsand triacylglycerol hydrolysis products.47,48 As there is ongoingdebate over its role in efficient cholesterol transport,49 wehypothesized that the main role of SR-BI in the intestine is tofacilitate the uptake of lipid micronutrients.32 Indeed, weshowed in Caco-2 cells that SR-BI is involved in the intestinaluptake of the carotenoid lutein,50 and this involvement hassince been extended to other provitamin51,52 and non-pro-vitamin carotenoids.53,54 Moreover, SR-BI was shown tomediate tocopherol uptake across the BBM in both Caco-2 andmice models.55 It was thus not surprising that our combinedapproach using Caco-2 cells, HEK cells transfected with SR-BI,mouse intestinal explants, and mice overexpressing SR-BI inthe intestine showed that SR-BI was also involved in vitamin Duptake.14 SR-BI is thus involved in the uptake of a broadvariety of molecules (cholesterol ester, carotenoids, and vita-mins E and D, among others) but not in the uptake of micellarretinol.52,56 Building on recent insights provided by LIMPIIcrystallization,57 it can be suggested that SR-BI interactswith the mixed micelles and facilitates the specific uptake ofcertain lipid molecules solubilized within them. This is inagreement with previous data suggesting that the role of SR-BIat the BBM is related to micelle binding.58

Another ubiquitous scavenger receptor of interest is CD36(Cluster Determinant 36).44 This protein is also expressed atthe BBM level of the duodenum and the jejunum59 and, muchlike SR-BI, it can interact with a broad variety of ligands fromlipoproteins to apoptotic cells.44 It has been implicated in awide array of cellular functions, but its main role at the intesti-nal level was thought to be related to fatty acid uptake.45

Surprisingly, the first observations in CD36-deficient micesuggested that it did not play a role in intestinal lipid absorp-tion after a lipid load,60 but a following study showed thatlipid secretion in the lymph was actually decreased inthe CD36-deficient mice. This discrepancy lies in the factthat CD36 also regulates chylomicron catabolism and impactschylomicron size, leading to chylomicron accumulation andthus masking the impaired lipid secretion.61 Indeed, in bothmice and humans,62 CD36 deficiency resulted in the intestinalsecretion of small intestinal lipoproteins. It was also suggestedthat in the enterocyte, CD36 enabled long-chain fatty acids tobe routed to the endoplasmic reticulum for chylomicronassembly. More recently, the in situ perfusion of mouseisolated intestinal loops — a technique maintaining theunstirred water layer, cell polarization and lymph/blood circu-lations — highlighted that the intestinal CD36 was not primar-ily involved in fatty acid uptake.63 The authors showed that thetransporter, possibly through ERK1/2-mediated signaling, wasactually involved in the adaptation of enterocyte metabolismto the postprandial lipid challenge by promoting the pro-duction of large triglyceride-rich lipoproteins that are rapidly

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cleared in the blood.63 As CD36 colocalizes with other proteinsinvolved in lipid endocytosis, such as caveolin-1 in lipidrafts,64,65 the suggestion was that the two proteins cooperatefor lipid transport. CD36 also plays a key role in lipid micro-nutrient intestinal uptake, as it is involved in β-caroteneuptake51 and is able to mediate vitamin D3 uptake in humantransfected HEK cells as well as in mouse internal explants.14

The last membrane transporter of interest for vitamin Dintestinal absorption is NPC1L1, a 135 kDa protein especiallyexpressed in the liver and at the plasma membrane of theintestinal cell.66–70 NPC1L1 was originally described as themain cholesterol and phytosterol transporter in the intestine.71

It was recently demonstrated that NPC1L1 is recycled betweenthe plasma membrane and the intracellular compartments viaan endocytotic pathway regulated by cellular cholesterol, wherecholesterol depletion would induce a relocalization of theprotein at the cell surface and thus increase cholesteroluptake.72 NPC1L1 was further shown to be involved in thetransport of vitamin E73,74 and possibly carotenoids, but notlycopene.54,75 As vitamin D3 displays a sterol structure, it wasagain not surprising that NPC1L1 was also shown to beinvolved, albeit moderately, in its intestinal uptake usingin vitro, ex vivo and in vivo mouse models.14

Note that the enterocyte is not a simple gate for nutrients toenter the body, as numerous proteins located at the apical sideof the cells can efflux molecules back to the lumen to regulateor inhibit their absorption. For example, the role of SR-BI isnot limited to uptake: we showed using Caco-2 cells that it isalso involved in the efflux of both vitamins D3

14 and E55

across the BBM. Cells pre-charged with vitamin D3 were able toefflux the vitamin back to the apical medium, especially whenmixed micelles were added as acceptors, and this efflux wassignificantly inhibited in the presence of SR-BI inhibitors (thechemical inhibitor Block-Lipid Transport 1 and/or blockingantibody).14

It is very likely that other transporters can efflux vitamin Dat the BBM. In particular, the ABCG5/G8 heterodimer is criticalto sterol homeostasis. Mutations in the genes encoding theseproteins cause β-sitosterolemia,76 a disease characterized byabnormally high levels of phytosterols in blood and tissuesdue to increased intestinal absorption and decreased secretionthrough the bile. The ABCG5/G8 complex acts as an effluxpump in the enterocyte where it mainly limits phytosterolabsorption. Interestingly, ABCG5 and ABCG8 can also trans-port cholesterol,77 but no data are available on vitamin D.

The fact that several lipid transporters are involved in theuptake and efflux of vitamin D and other lipid micronutrientsat the apical membrane likely explains why these moleculescompete for apical uptake. Accordingly, we have shown thatvitamin D competes with either cholesterol/phytosterols orvitamin E.14,15

Very recently, we showed that high vitamin K concen-trations and vitamin A also inhibited vitamin D absorption inCaco-2 cells (data submitted). While it is likely that vitamins Dand K share a common absorption pathway, vitamin Aprobably does not.52 Further investigations are needed to

understand the mechanisms underlying this inhibitionmechanism.

Vitamin D transport across the enterocyte and secretionthrough the basolateral membrane

Vitamin D3 is theoretically incorporated into the chylomicronswithout any chemical modification,78,79 even though one studydid recover vitamin D3 esters in rat plasma, as discussedabove.20 Data on the intracellular transport of vitamin D in theintestinal cell remain scarce. An intracellular binding proteinhas been characterized in rat enterocytes.80 This protein isnamed cytosolic vitamin D metabolite binding protein (cDBP).As it preferentially binds 25-hydroxyvitamin D, it has beensuggested that it may transport this metabolite across theenterocyte via the chylomicron-independent route.81 However,vitamin D is mainly ingested in its D3 form that is incorpor-ated into chylomicrons, and there are no data on theexpression of cDBP or any other vitamin D binding protein inhuman enterocytes or on their putative role in vitamin D3

transport across the enterocyte. We previously suggested thatcDBP could stick to membrane transporters (i.e. SR-BI, CD36or NPC1L1) and be internalized with them to transfer vitaminD either to other intracellular transporters or to organellemembranes.32

It is assumed that most of the newly-absorbed lipid micro-nutrients are incorporated into chylomicrons that are secretedinto the lymph (apolipoprotein B-dependent route), although agrowing body of evidence now suggests that the intestinesecretes significant amounts of HDL during the postprandialperiod via ATP Binding Cassette A1 (ABCA1).32 There are nodata on this putative apolipoprotein B-independent secretionof vitamin D3 by the enterocyte, but the belief is that the 25-hydroxyvitamin D that can be found and absorbed from foodsis mainly absorbed by the portal route.82 Interestingly,25-hydroxyvitamin D was reported to have higher bioavailabilitythan vitamins D3 and D2,

83,84 especially against a backgroundof fat malabsorption or intestinal pathologies,18,85 whichsuggests that this form may be very useful as a supplement torestore vitamin D status in deficient patients.

The different uptake and secretion pathways of vitamin Dacross the enterocyte are summarized in Fig. 2.

Conclusion

The intraluminal fate and molecular mechanisms of the intes-tinal absorption of vitamin D are clearly still only partiallyunderstood. The discovery of vitamin D intestinal transporterswith broad substrate specificity has raised numerous questionson the potential interactions with dietary lipids during theabsorption process. Moreover, micelle binding to the mem-brane receptors is probably a key step of fat-soluble micro-nutrient entry into the enterocyte. Finally, the differences inexpression levels and the existence of functional polymorph-isms in the genes encoding these proteins may explain muchof the observed large interindividual variation in postprandial

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responses to vitamin D.86 Further dedicated investigations areneeded to address this presumption.

List of abbreviations

ABCA1 ATP Binding Cassette A1ABCG5 ATP Binding Cassette G5ABCG8 ATP Binding Cassette G8CD36 Cluster Determinant 36NPC1L1 Niemann–Pick C1-Like 1SR-BI Scavenger Receptor Class B Type 1BBM Brush-border membrane.

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Fig. 2 Proteins involved in vitamin D transport across the enterocyte.? = unidentified transporter, ---- = unidentified pathway. Vitamin D (vit D)is taken up from mixed micelles, and maybe from vesicles and/orprotein(s), by apical membrane transporters: SR-BI, CD36 and NPC1L1. Afraction of vitamin D likely enters the cell by passive diffusion, especiallywhen vitamin D is administered at pharmacological doses. A part ofvitamin D may then be effluxed back to the intestinal lumen via apicalmembrane transporters (at least SR-BI and possibly others). Anotherfraction is transported to the chylomicron incorporation site. The intra-cellular transport of vitamin D may involve binding proteins, but nonehas yet been clearly identified. Vitamin D in its free form is then secretedin the lymph into chylomicrons (apolipoprotein B-dependent route),although other secretion pathways such as a non-apolipoproteinB-dependent route via ABCA1 and HDL may exist.

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