ArticlePDF AvailableLiterature Review

Absorption of Vitamin A and Carotenoids by the Enterocyte: Focus on Transport Proteins


Abstract and Figures

Vitamin A deficiency is a public health problem in most developing countries, especially in children and pregnant women. It is thus a priority in health policy to improve preformed vitamin A and/or provitamin A carotenoid status in these individuals. A more accurate understanding of the molecular mechanisms of intestinal vitamin A absorption is a key step in this direction. It was long thought that β-carotene (the main provitamin A carotenoid in human diet), and thus all carotenoids, were absorbed by a passive diffusion process, and that preformed vitamin A (retinol) absorption occurred via an unidentified energy-dependent transporter. The discovery of proteins able to facilitate carotenoid uptake and secretion by the enterocyte during the past decade has challenged established assumptions, and the elucidation of the mechanisms of retinol intestinal absorption is in progress. After an overview of vitamin A and carotenoid fate during gastro-duodenal digestion, our focus will be directed to the putative or identified proteins participating in the intestinal membrane and cellular transport of vitamin A and carotenoids across the enterocyte (i.e., Scavenger Receptors or Cellular Retinol Binding Proteins, among others). Further progress in the identification of the proteins involved in intestinal transport of vitamin A and carotenoids across the enterocyte is of major importance for optimizing their bioavailability.
Content may be subject to copyright.
Nutrients 2013, 5, 3563-3581; doi:10.3390/nu5093563
ISSN 2072-6643
Absorption of Vitamin A and Carotenoids by the Enterocyte:
Focus on Transport Proteins
Emmanuelle Reboul
INRA, UMR1260, Nutrition, Obesity and Risk of Thrombosis, Marseille F-13385, France;
E-Mail:; Tel.: +33-4-91-29-41-03; Fax: +33-4-91-78-21-01
INSERM, UMR1062, Marseille F-13385, France
Aix-Marseille University, Marseille F-13385, France
Received: 24 June 2013; in revised form: 19 August 2013 / Accepted: 26 August 2013 /
Published: 12 September 2013
Abstract: Vitamin A deficiency is a public health problem in most developing countries,
especially in children and pregnant women. It is thus a priority in health policy to improve
preformed vitamin A and/or provitamin A carotenoid status in these individuals. A more
accurate understanding of the molecular mechanisms of intestinal vitamin A absorption is a
key step in this direction. It was long thought that β-carotene (the main provitamin A
carotenoid in human diet), and thus all carotenoids, were absorbed by a passive diffusion
process, and that preformed vitamin A (retinol) absorption occurred via an unidentified
energy-dependent transporter. The discovery of proteins able to facilitate carotenoid uptake
and secretion by the enterocyte during the past decade has challenged established
assumptions, and the elucidation of the mechanisms of retinol intestinal absorption is in
progress. After an overview of vitamin A and carotenoid fate during gastro-duodenal
digestion, our focus will be directed to the putative or identified proteins participating in
the intestinal membrane and cellular transport of vitamin A and carotenoids across the
enterocyte (i.e., Scavenger Receptors or Cellular Retinol Binding Proteins, among others).
Further progress in the identification of the proteins involved in intestinal transport of
vitamin A and carotenoids across the enterocyte is of major importance for optimizing
their bioavailability.
Keywords: retinol; carotenes; xanthophylls; bioavailability; transporters; intestinal absorption
Nutrients 2013, 5 3564
List of abbreviations
ARAT: Acyl-CoA Acyl Transferase; ABCA1: ATP Binding Cassette A1; ABCG5: ATP Binding
Cassette G5; ABCG8: ATP Binding Cassette G8; BBM: Brush Border Membrane; BCMO1:
β-carotene-15,15-monooxygenase; BCDO2: β-carotene-9,10-dioxygenase; CBP: Carotenoid-Binding
protein; CD36: Cluster Determinant 36; CRBPII: Cellular Retinol Binding Protein II; HR-LBP:
Human Retinal Lutein-Binding Protein; ISX: Intestine-Specific Homebox; L-FABP: Liver Fatty-Acid-
Binding Protein; LRA: Lecithin Retinol Acyl Transferase; NPC1L1: Niemann-Pick C1-Like 1; RBP:
Retinol Binding Protein; RBPR2: RBP-receptor 2; SR-BI: Scavenger Receptor class B type 1; STRA6:
STimulated by Retinoic Acid 6.
1. Introduction
Vitamin A is essential for normal cell growth, cell differentiation, immunological functions and
vision [1]. However, vitamin A deficiency is still a public health problem in more than half of all
countries, especially in Africa and South-East Asia where meat intake is low, and particularly in young
children and pregnant women. Therefore, it is a priority in health policy to improve preformed vitamin
A and/or provitamin A carotenoid status of these population subgroups. A precise understanding of the
molecular mechanisms involved in vitamin A intestinal absorption is a key step in this direction.
Vitamin A is found in animal-based foods as retinyl esters (mainly retinyl palmitate). In fruits and
vegetables, it occurs as provitamin A carotenoids (mainly β-carotene, α-carotene and β-cryptoxanthin),
which can be cleaved and metabolized into retinol after absorption by the intestinal cells (Table 1).
Nonprovitamin A carotenoids, such as lutein and lycopene, share similar digestion/absorption pathways
with provitamin A carotenoids: they will thus be included in this review when appropriate (Table 1).
The fundamental mechanisms of preformed vitamin A and carotenoid absorption were first studied
40 years ago using rat everted intestinal sacs [2–4]. The data obtained suggested that carotenoids were
absorbed by passive diffusion, while preformed A was absorbed via (a) carrier-dependent proteins.
Recent studies completed over the past ten years have once again addressed these hypotheses, and
have shown that the mechanisms of retinol and carotenoid absorption are actually more complex than
previously thought. Although a passive diffusion may occur at pharmacological concentrations of
these compounds, a protein-mediated transport is clearly involved at dietary doses.
After an overview of the fate of retinol and carotenoid in the human upper gastrointestinal lumen,
we will focus on the putative or identified proteins participating in the intestinal membrane and
cellular transport of vitamin A and carotenoids across the enterocyte identified until 2013.
2. Overview of Vitamin A and Carotenoid Fate during the Digestion Process
Fat-soluble micronutrients including vitamin A and carotenoids are assumed to follow the fate of
lipids in the upper gastrointestinal tract [5], and their absorption presumably occurs in the upper half of
the small intestine.
Nutrients 2013, 5 3565
Table 1. Main dietary retinoids and carotenoids.
Molecular structure
Main food sources
(µg/100 g) [6–9]
proteins in the
Liver: 10,800–23,500
Fatty fish: 8001000
Butter: 700
Raw carrot: 8840
Canned carrot: 5780
Cooked spinach: 5240
Cooked carrot: 468
Orange juice: 880
Mandarin juice: 920
Cooked spinach: 7040
Lettuce: 2640
Tomato sauce: 15,920
Tomatoes: 3030
Watermelon: 4870
The first phase of the process of digestion/absorption is the dissolution of carotenoids [10,11] and
vitamin A [12] in the fat phase of the meal. This phase is emulsified into lipid droplets in the stomach
and duodenum. The size of the droplets has apparently no effect on the efficiency of the absorption of
vitamin A in healthy humans, and no degradation or absorption of vitamin A has been detected at the
stomach level [11,12].
It seems that only the free forms of fat-soluble vitamins and carotenoids are absorbed by the
intestinal mucosa, suggesting that the esterified forms are first hydrolyzed. Studies on this topic mainly
concern retinyl esters. Their hydrolysis may begin in the stomach, where gastric lipase hydrolyses
about 17.5% of the triacylglycerols [13]. However, the data obtained in healthy subjects have shown
that gastric lipase does not significantly hydrolyse retinyl palmitate [12]. The hydrolysis of esters of
vitamin A thus occurs essentially in the duodenum. The pancreatic juice contains two main enzymes
that could perform this hydrolysis: cholesterol ester hydrolase (CEH) and pancreatic lipase (LP). It has
been shown that the CEH can achieve this hydrolysis in vitro [14–17]. However, studies in
CEH-deficient mice showed that this enzyme was not significantly involved in the hydrolysis of retinyl
esters in vivo [18,19]. Since some studies showed that the LP could hydrolyse retinyl palmitate
in vitro [18,20–22] and as the CEH was not involved, it is assumed that the luminal hydrolysis of
Nutrients 2013, 5 3566
retinyl esters is achieved by the LP, together with the pancreatic lipase-related protein 2 [22]. The
enzymes described above are all good candidates for the hydrolysis of esters of carotenoids. In a study
on the bioavailability of lutein esters, it was suggested that CEH could allow the release of free
lutein [17]. The esters that have not been hydrolyzed by LPs or CEH may be cleaved by mucosal
enzymes, given that a retinyl ester hydrolase probably due to a phospholipase B [23] was identified at
the brush border membrane (BBM) level of rat and human intestine [24,25]. Finally, it is conceivable
that some esters are taken up intact by the intestinal cell and hydrolyzed intracellularly [8].
During the process of digestion, carotenoids and fat-soluble vitamins are incorporated with other
lipids into the mixed micelles [5], presumably necessary for their absorption by the enterocyte. Mixed
micelles are a mixture of phospholipids, cholesterol, lipid digestion products (such as free fatty acids,
monoacylglycerols and lysophospholipids) and bile salts. Fat-soluble micronutrient transfer to mixed
micelles during dietary lipid lipolysis by the gut lipases can be affected by several factors, including
the micronutrient molecular structure [5,26], pH and bile lipid concentration [27,28], and the presence
of a minimal amount of dietary fat [29]. Dietary fat stimulates pancreatic juice and biliary secretion,
both necessary for lipid digestion and micelle formation, and provide the lipids necessary to structure
the mixed micelles. It is assumed that the higher the percentage of lipid micronutrient incorporated in
micelles (a percentage called “bioaccessibility”), the higher its absorption efficiency. Although it is
assumed that retinol and carotenoids globally transfer to the mixed micelles, some may be
incorporated into other proteic or lipid structures (vesicles and liposomes) present in the same aqueous
fraction. It has been shown that vitamin A can be incorporated in phospholipid bilayers [30,31] and
that vesicle stability to the bile salt deoxycholate is enhanced by the presence of vitamin A [30]. Also,
β-lactoglobulin, a lipocalin recovered in cow milk, is able to bind both retinol and β-carotene [32–35].
It is therefore possible that some proteins found in the diet and/or the pancreatic/biliary secretions bind
a fraction of retinol and/or carotenoids and transport them to the brush border membrane (BBM) of the
enterocyte. The mechanisms of absorption may then depend on their associated vehicles. In the case of
mixed micelles, the particles are isolated from the rest of the intestinal contents in the unstirred water
layer of the glycocalyx area and dissociated by pH effect. Indeed, the acidic microclimate of this area
promotes the protonation of fatty acids. This phenomenon reduces fatty acid solubility in micelles,
causing their release and thus micelle dissociation near the BBM. Components released are then
picked up by various more or less specific systems responsible for their uptake by the enterocyte.
Retinol absorption efficiency ranges between 75% [36] and 100% [37–42]. Absorption efficiency of
β-carotene ranges from 3% to 90% for [43–45]. Nevertheless, it is assumed that retinol displays a
higher absorption efficiency than carotenoids, as confirmed by recent data obtained in our laboratory
using Caco-2 cells. Micellar retinol absorption efficiency was around 30% in 1 h, but less than 5% for
micellar provitamin A carotenoids [46]. This may be explained by the presence of an efficient specific
transporter for retinol, whereas provitamin A carotenoids are absorbed via non-specific transporters
(see below).
Nutrients 2013, 5 3567
3. Absorption of Vitamin A and Carotenoids by the Enterocyte (Figure 1)
3.1. Apical Uptake and Efflux
Although some authors have suggested that free retinol (from 0.5 to 130 µM) enters intestinal cells
by simple diffusion [47], it has long been acknowledged that retinol uptake occurs by a saturable
carrier-mediated process at physiological doses, whereas it occurs by passive diffusion at
pharmacological doses in Caco-2 cells [48] and in rats [2,4]. A good candidate for retinol specific
uptake by intestinal cells was the protein STRA6 (STimulated by Retinoic Acid 6). This 74 kDa
multi-transmembrane transporter has been identified as a specific receptor for RBP (Retinol-Binding
Protein) [49]. Among other tissues, this protein is found in the intestine during development, although
it is not clear whether it persists in adults [50]. Even so, it can still be suggested that STRA6 may be
responsible for the uptake of either micellar retinol or retinol bound to protein-like β-lactoglobulin
(see Section 1), especially because this protein shares similar amino acid sequence and tertiary
structure with RBP. It has also been shown that STRA6 acts as a bidirectional transporter of
retinol [51]. Very recently, a new candidate has been discovered: RBPR2 (RBP4-receptor 2).
Structurally related to STRA6, this ubiquitous transporter is clearly expressed in the intestine, where it
may play a role in dietary retinol uptake [52].
Concerning carotenoids, it has long been assumed that their intestinal absorption occurs by passive
diffusion. In living unanesthetized rats, β-carotene absorption was shown to be linear between 0.5 and
11 mM. Also, an increase in the perfusate hydrogen ion concentrations (which should decrease cell
membrane resistance to micelle diffusion), additions of different types of fatty acids, or an increase in
the perfusate flow rate (which should diminish the thickness of the unstirred water layer) increased its
absorption. Conversely, an increase in taurocholate concentration did not change it. These observations
led the authors to conclude that β-carotene absorption was driven by passive diffusion [3].
However, a close look at the data obtained by Hollander and coworkers shows a saturation of
absorption in the distal part of the intestine. Additionally, the hypothesis of a passive diffusion
mechanism for carotenoid uptake cannot explain (i) the high inter-individual variability in absorption
observed in human studies [53,54]; (ii) the isomer selectivity and the competition for absorption
between carotenoids [55], or between lutein and carotenoids or vitamin, and vice versa [56,57]
observed in cell models; or (iii) the competition between vitamin E and the carotenoid canthaxanthin
described in rats [58]. Finally, the identification of the Drosophila gene ninaD encoding a class B
scavenger receptor essential for carotenoid cellular distribution [59] also argues in favor of the
existence of putative membrane transporters of carotenoids.
Nutrients 2013, 5 3568
Figure 1. Proteins involved in uptake, transport and secretion pathways of vitamin A and
carotenoids across the enterocyte.
Vit = vitamin; βC = β-carotene; αC = α-carotene, βC = β-cryptoxanthine, Lut = lutein;
Lyc = lycopene; Car = carotenoids; A = retinol putative specific transporter; B = unidentified apical
transporter; C = passive diffusion; D = unidentified basolateral efflux transporter; ? = putative
pathway. Carotenoids are captured from mixed micelles by apical membrane transporters: SR-BI,
CD36 and NPC1L1. Apical membrane proteins involved in apical uptake of retinol have not yet
been identified. A fraction of vitamin A and carotenoids may then be effluxed back to the intestinal
lumen via apical membrane transporters (SR-BI and possibly other transporters). Another fraction
is transported to the site where they are incorporated into chylomicrons. Some proteins may be
involved in intracellular transport of carotenoids, but none has been clearly identified. Conversely,
CRBPII has clearly been described as involved in intracellular transport retinol. Retinyl esters and
carotenoids are secreted in the lymph into chylomicrons, while a part of the more polar metabolites
may be secreted by the portal route. It is suggested that free retinol can also be secreted at the
basolateral side via ABCA1 (apoAI pathway).
Nutrients 2013, 5 3569
Several lipid transporters playing a role in carotenoid uptake by the intestinal cell have since been
identified. The first one to be highlighted was the Scavenger Receptor class B type I: SR-BI. This
ubiquitous 80 kDa single-chain transmembrane glycoprotein is found on the BBM of enterocytes from
the duodenum to the colon [60]. First identified as able to bind lipoproteins [61], SR-BI can also
facilitate the selective entry into the cell of a large number of ligands, from free and esterified
cholesterol to phospholipids and triacylglycerol hydrolysis products [62,63]. However, the effective
role of SR-BI in the intestine is probably to facilitate the uptake of lipids other than cholesterol [64]. A
first study performed in our laboratory identified this protein as playing a role in the intestinal uptake
of the carotenoid lutein in Caco-2 cells [65]. This involvement has since been extended to other
carotenoids such as β-carotene [66], zeaxanthin [67] and lycopene [68] in various other tissues.
However, SR-BI does not seem to be involved in the uptake of micellar retinol [46].
Another ubiquitous scavenger receptor of interest is CD36 (Cluster Determinant 36). This other
90 kDa single chain-membrane glycoprotein is also expressed at the BBM level of the duodenum and
the jejunum [61] and displays a broad substrate specificity [69]. It is assumed to play a key role in fatty
acid uptake in the intestine [70]. It was shown that lipid secretion in the lymph was decreased in
CD36-deficient mice [71], as CD36 probably allows the routing of the long-chain fatty acids to the
endoplasmic reticulum for chylomicron assembly in the enterocyte. Although the underlying
mechanism is unknown, it may be linked to the intracellular traffic of the protein between the plasma
membrane and the organelles. CD36 was involved in β-carotene uptake using transfected COS cells
and mouse BBM vesicles [66], in agreement with the finding that a CD36-related protein is involved
in selective carotenoid transport in Bombyx mori [72]. In addition, CD36 has been shown to be
involved in both lycopene and lutein uptake in mouse 3T3-L1 adipocytes and in mouse adipose tissue
cultures [73]. It is noteworthy that CD36 colocalizes with other proteins such as caveolin-1 in lipid
rafts [74]. It is therefore possible that a cooperation occurs between these proteins for lipid
micronutrient uptake.
Among the cholesterol membrane transporters, one of the last to be identified was NPC1L1, a
135 kDa protein widely expressed in human tissues including the plasma membrane of the intestinal
cell [75–79]. NPC1L1 has been described as the main cholesterol and phytosterol transporter in the
intestine [76,77,80]. NPC1L1 was suggested to be involved in carotenoid intestinal uptake, as its
specific inhibitor ezetimibe decreased α- and β-carotene uptake by 50%, β-cryptoxanthin and lycopene
uptake by 20%, and lutein and zeaxanthin uptake by 7% in Caco-2 cells [81]. Even though this result
was confirmed for lutein [82], another study showed that neither ezetimibe nor a blocking antibody
raised against NPC1L1 impaired lycopene absorption in the same cells [68].
No clear data are currently available on carotenoid apical efflux across the BBM of the intestinal
cell. Nevertheless, as SR-BI can function in both directions in the intestine [83], and as it was shown to
be involved in both vitamin D [84] and E [85] efflux throughout Caco-2 cell apical membrane, we
suggest that a similar phenomenon can exist for carotenoids. It is also very likely that other
transporters, such as the ATP-Binding Cassette (ABC) transporters can act as efflux pumps of lipid
micronutrients through the BBM. As a matter of fact, it has been suggested that ABCG5 plays a role in
the plasma response to dietary carotenoids [86].
Nutrients 2013, 5 3570
3.2. Intracellular Metabolism
Once taken up by the enterocyte, retinol is esterified in retinyl esters by LRAT (Lecithin Retinol
Acyl Transferase) and ARAT (Acyl-CoA Acyl Transferase) [87]. The use of LRAT-deficient mice
indicated that this enzyme played the most crucial role regarding retinol esterification [88]. The main
ester formed is retinyl palmitate, but significant amounts of retinyl oleate, linoleate, and stearate can be
found in mice [89] and humans [90].
Interestingly, there is a synergy between STRA6 and LRAT expression [91], although the presence
of LRAT is not strictly necessary for retinol influx into the cells [92]. We can hypothesize that such a
synergy may also exist with another retinol transporter close to STRA6. If the intestinal cells express
both STRA6 or a related transporter and LRAT, then they can theoretically take up more retinol than
cells expressing each protein individually, the conversion of retinol into retinyl ester by LRAT within
the cell maintaining the driving force for STRA6-mediated retinol uptake.
After uptake by the enterocyte, a substantial quantity of carotenoids is not metabolized (up to 40%
of the dietary intake) [93]. A fraction of provitamin A carotenoids is cleaved into retinal by the
cytoplasmic protein BCMO1 (β-carotene-15,15-monooxygenase). Retinal can then be converted to
retinol and then to retinyl esters. They can also be cleaved, together with non-provitamin A
carotenoids, into apocarotenoids by mitochondrial BCDO2 (β-carotene-9,10-dioxygenase) [94]. In
order to exhibit a provitamin A activity, a carotenoid should display at least both one β-ionone ring and
an appropriate methyl group in its polyene chain. Thus in theory, one molecule of β-carotene can give
rise to two molecules of retinol, while α-carotene and β-cryptoxanthine will give one retinol molecule
only. In practice, β-carotene is effectively the most potent vitamin A precursor, α-carotene and
β-cryptoxanthine showing 30% to 50% of provitamin A activity [95,96]. Apparently, no cis-trans
isomerization of β-carotene occurs in intestinal cells [55], suggesting that the 9-cis isomerization
reported in vivo [97] occurs in the gastrointestinal lumen.
3.3. Cytosolic Transport
Intracellular transport of retinol (and its metabolites retinal and retinoic acid) involve
retinoid-binding proteins in most tissues [98,99]. CRBPII (Cellular Retinol-Binding Protein II) is
mainly expressed in the absorptive cells of the intestine and is one of the most abundant soluble
proteins in the jejunum, representing up to 1% of the total enterocyte cytosolic proteins [100]. It was
first shown that its mRNA expression increased in the small intestine of rats under a retinoid-deficient
diet [101]. Studies using CRBPII-deficient mice then definitively acknowledged CRBPII as playing an
important role in vitamin A intestinal absorption and metabolism [102,103]. The involvement of
CRBPI (Cellular Retinol-Binding Protein I) cannot be ruled out, as this protein is also found in the
enterocyte [104], but no mechanistic evidence is available to date. STRA6 may be able to couple to
both CRBPI and CRBPII depending on the conditions. However, although CRBPII is considered to
facilitate the uptake of free retinol by the enterocyte, it has been shown to couple efficiently to STRA6
for retinol efflux [92].
Concerning carotenoids, a cytosolic carotenoid-binding protein (CBP) has been identified in the
midgut of the silkworm Bombyx mori [72,105]. Interestingly, the lutein-binding protein HR-LBP
Nutrients 2013, 5 3571
present in human retina (Human Retinal Lutein-Binding Protein) cross-reacts with antibodies raised
against Bombyx mori silkworm CBP. If expressed in human enterocytes, LBP would thus be a good
candidate as an intracellular transporter of xanthophylls.
Other candidates for the intracellular transport of carotenoids are the apical membrane transporters
trafficking between the apical membrane and the cellular organelles. NPC1L1 has been observed in
endosomes, perinuclear regions, lysosomes and mitochondria of the human intestinal cell [106,107].
CD36 has been detected in both the apical membrane and the Golgi apparatus [108]. Finally, SR-BI
has also been found at the apical and basolateral membranes of enterocytes, as well as in cytoplasmic
lipid droplets and in tubulovesicular membranes. Mainly localized in the microvillus membrane in the
fasting state, SR-BI seems to be endocytosed after a dietary fat load [109]. Some carotenoids may bind
to these apical transporters, or to membrane microdomains close to these transporters, and traffic with them
within the cell to be transferred to either other intracellular transporters or to intracellular membranes.
Finally, Fatty Acid-Binding Proteins (FABPs) may be able to participate in the intracellular
transport of carotenoids as they display a broad ligand specificity [110,111]. Two FABPs exhibiting a
high-affinity binding of long-chain fatty acids are co-expressed in the human enterocyte: intestinal
FABP (IFABP) and liver FABP (LFABP) [112,113], and it is suggested that IFABPs allow a specific
trafficking of their ligands to their respective metabolic fates. Although dedicated studies are needed to
verify whether IFABP and/or LFABP are involved in carotenoid metabolism, it is noteworthy that a
genetic association study found that a genetic variant in IFABP was associated with fasting plasma
lycopene concentrations [114].
3.4. Basolateral Secretion
In the postprandial period, it is assumed that the major fraction of vitamin A and carotenoids are
incorporated into chylomicrons that are secreted into the lymph [115,116], vitamin A being recovered
as retinyl esters, while carotenoids are recovered in their free forms [90,117]. It was shown in Caco-2
cells that only newly-synthesized retinyl esters could be incorporated into chylomicrons [47], which
suggests that retinyl ester synthesis is coupled to chylomicron assembly.
Interestingly, it has been shown that in the fasting state, free retinol unassociated with lipoproteins
could be secreted by Caco-2 cells [115]. In addition, in patients who do not assemble and secrete
chylomicrons (abetalipoproteinemia), massive retinol supplementation can reverse retinal abnormality
due to retinol deficiency [118], indicating that a pathway other than the chylomicron route may
be involved in retinol absorption. Additionally, it is now clear that the intestine is also able to
secrete large amounts of HDL during the postprandial period via an ABCA1 transporter-dependent
pathway [119]. ABCA1 is a 240 kDa protein playing a pivotal role in reverse cholesterol transport,
although the molecular mechanisms involved in this phenomenon are still matter of debate [120].
ABCA1 is strongly expressed in the intestine [121], especially at the basolateral side of the cell [122].
Experiments performed in ABCA1-deficient mice showed that it was not significantly involved in the
intestinal secretion of retinyl esters [89]. It has been suggested that it could facilitate the efflux of free
retinol from intestinal cells [47]. The authors show that both glyburide (an inhibitor of ABC
transporters) and SiRNA targeting complementary DNA of ABCA1 partly inhibited retinol basolateral
Nutrients 2013, 5 3572
efflux. However, glyburide is far from being a highly specific inhibitor [123], so this result needs
further confirmation.
4. Consequences of the Involvement of Vitamin A and Carotenoid Intestinal Transporters
A first factor that may modulate the expression and/or activity of intestinal proteins involved in
vitamin A and carotenoid absorption is vitamin A and carotenoids themselves, through a feedback
regulation. For example, using both mouse models and human cell lines, it was shown that retinoic
acid produced from dietary precursors induced the expression of the intestinal transcription factor ISX
(Intestine-Specific Homebox) that repressed the expression of both SR-B1 and BCMO1 [124].
Another example is in Caco-2 cells, where CRBPII expression was increased after retinoic acid
treatment [125]. Many transporters can also be regulated by some of their ligands other than retinoids
and carotenoids. This is the case for NPC1L1 and the ATP-binding cassette proteins ABCA1, ABCG5
and ABCG8, which are downregulated under cholesterol-free high-fat diets [126]. It was also shown
that heart CD36 and hepatic SR-BI expressions were regulated by dietary fat [127,128], and that
CRBPII was modulated by diets containing long-chain fatty acids [101]. It is thus possible that the
effect of fat on vitamin A and carotenoid absorption described in the first section is actually partly
linked to a modulation of the expression of transporters involved in their absorption.
A second factor is the possible existence of genetic variants in genes encoding transport proteins
that may affect vitamin A and carotenoid absorption efficiency. Genetic variations leading to
modifications in the promoter region of the gene or within the amino acid sequence of the protein may
affect its expression and/or activity, and thus its ability to absorb/transport its ligands. This is
supported by the broad inter-individual variability observed for carotenoid assimilation [53], and by
the associations found between genetic variants SR-BI and CD36 and blood concentrations of
carotenoids [129,130]. However, these associations may be due to the effect of genetic variants on the
expression or activity of the proteins in tissues other than the intestine (i.e., the liver). β-Carotene
“low-converter” phenotypes, probably due to genetic variation in the BCMO1 gene, have been
reported in several studies [94]. If this hypothesis is supported in the future, it may be worthwhile
taking it into account to provide adequate dietary amount of vitamin A and carotenoid to
“low responder” or “high responder” phenotypes due to different transport and/or conversion efficacy.
It is also interesting to note that as some of the transporters described above are involved in the
absorption of several lipid micronutrients (e.g., SR-BI participate in the absorption of carotenoids, but
also of vitamin E [85] and vitamin D [84]), some subjects may be at risk of micronutrient
multideficiency. Adequate recommended dietary allowances would then be a first step towards
personalized nutrition based on the genetic characteristics of individuals.
5. Conclusions
To conclude, the full understanding of vitamin A and carotenoid absorption by the enterocyte is still
in progress. Although some specific proteins such as the cytosolic CRBPII, and several non-specific
transporters such as SR-BI, NPC1-L1, and ABCA1 have been identified, other transporters such as the
dietary vitamin A apical membrane transporter remain to be identified.
Nutrients 2013, 5 3573
Conflicts of Interest
The authors declare no conflict of interest.
1. Gerster, H. Vitamin A—Functions, dietary requirements and safety in humans. Int. J. Vitam.
Nutr. Res. 1997, 67, 71–90.
2. Hollander, D.; Muralidhara, K.S. Vitamin A1 intestinal absorption in vivo: Influence of luminal
factors on transport. Am. J. Physiol. Gastrointest. Liver Physiol. 1977, 232, E471–E477.
3. Hollander, D.; Ruble, P.E. Beta-carotene intestinal absorption: Bile, fatty acid, pH, and flow rate
effects on transport. Am. J. Physiol. 1978, 235. E686–E691.
4. Hollander, D. Intestinal absorption of vitamin A, E, D, and K. J. Lab. Clin. Med. 1981, 97,
5. Borel, P. Factors affecting intestinal absorption of highly lipophilic food microconstituents
(fat-soluble vitamins, carotenoids and phytosterols). Clin. Chem. Lab. Med. 2003, 41, 979–994.
6. Martin, A. Apports Nutritionnels Conseillés Pour La Population Française, 3rd ed.; Tec & Doc
Lavoisier: Paris, France, 2001; p. 605.
7. Reboul, E.; Richelle, M.; Perrot, E.; Desmoulins-Malezet, C.; Pirisi, V.; Borel, P.
Bioaccessibility of carotenoids and vitamin E from their main dietary sources. J. Agric. Food
Chem. 2006, 54, 8749–8755.
8. Dhuique-Mayer, C.; Borel, P.; Reboul, E.; Caporiccio, B.; Besancon, P.; Amiot, M.J.
Beta-cryptoxanthin from citrus juices: Assessment of bioaccessibility using an in vitro
digestion/Caco-2 cell culture model. Br. J. Nutr. 2007, 97, 883–890.
9. Hedren, E.; Diaz, V.; Svanberg, U. Estimation of carotenoid accessibility from carrots
determined by an in vitro digestion method. Eur. J. Clin. Nutr. 2002, 56, 425–430.
10. Borel, P.; Grolier, P.; Armand, M.; Partier, A.; Lafont, H.; Lairon, D.; Azais-Braesco, V.
Carotenoids in biological emulsions: Solubility, surface-to-core distribution, and release from
lipid droplets. J. Lipid Res. 1996, 37, 250–261.
11. Tyssandier, V.; Reboul, E.; Dumas, J.F.; Bouteloup-Demange, C.; Armand, M.; Marcand, J.;
Sallas, M.; Borel, P. Processing of vegetable-borne carotenoids in the human stomach and
duodenum. Am. J. Physiol. Gastrointest. Liver Physiol. 2003, 284, G913–G923.
12. Borel, P.; Pasquier, B.; Armand, M.; Tyssandier, V.; Grolier, P.; Alexandre-Gouabau, M.C.;
Andre, M.; Senft, M.; Peyrot, J.; Jaussan, V.; et al. Processing of vitamin A and E in the human
gastrointestinal tract. Am. J. Physiol. Gastrointest. Liver Physiol. 2001, 280, G95–G103.
13. Carrière, F.; Barrowman, J.A.; Verger, R.; Laugier, R. Secretion and contribution to lipolysis of
gastric and pancreatic lipases during a test meal in humans. Gastroenterology 1993, 105,
14. Lombardo, D.; Guy, O. Studies on the substrate specificity of a carboxyl ester hydrolase from
human pancreatic juice. II. Action on cholesterol esters and lipid-soluble vitamin esters.
Biochim. Biophys. Acta 1980, 611, 147–155.
Nutrients 2013, 5 3574
15. Zahalka, H.A.; Shee; Cheng, C.; Burton, G.W.; Ingold, K.U. Hydrolysis of stereoisomeric
alpha-tocopheryl acetates catalyzed by bovine cholesterol esterase. Biochim. Biophys. Acta 1987,
921, 481–485.
16. Lauridsen, C.; Hedemann, M.S.; Jensen, S.K. Hydrolysis of tocopheryl and retinyl esters by
porcine carboxyl ester hydrolase is affected by their carboxylate moiety and bile acids. J. Nutr.
Biochem. 2001, 12, 219–224.
17. Breithaupt, D.E.; Bamedi, A.; Wirt, U. Carotenol fatty acid esters: Easy substrates for digestive
enzymes? Comp. Biochem. Physiol. B Biochem. Mol. Biol. 2002, 132, 721–728.
18. Van Bennekum, A.M.; Li, L.; Piantedosi, R.; Shamir, R.; Vogel, S.; Fisher, E.A.; Blaner, W.S.;
Harrison, E.H. Carboxyl ester lipase overexpression in rat hepatoma cells and CEL deficiency in
mice have no impact on hepatic uptake or metabolism of chylomicron-retinyl ester. Biochemistry
1999, 38, 4150–4156.
19. Weng, W.; Li, L.; Van Bennekum, A.M.; Potter, S.H.; Harrison, E.H.; Blaner, W.S.; Breslow, J.L.;
Fisher, E.A. Intestinal absorption of dietary cholesteryl ester is decreased but retinyl ester
absorption is normal in carboxyl ester lipase knockout mice. Biochemistry 1999, 38, 4143–4149.
20. Erlanson, C.; Borgstrom, B. The identity of vitamin A esterase activity of rat pancreatic juice.
Biochim. Biophys. Acta 1968, 167, 629–631.
21. Lindstrom, M.B.; Sternby, B.; Borgstrom, B. Concerted action of human carboxyl ester lipase
and pancreatic lipase during lipid digestion in vitro: Importance of the physicochemical state of
the substrate. Biochim. Biophys. Acta 1988, 959, 178–184.
22. Reboul, E.; Berton, A.; Moussa, M.; Kreuzer, C.; Crenon, I.; Borel, P. Pancreatic lipase and
pancreatic lipase-related protein 2, but not pancreatic lipase-related protein 1, hydrolyze retinyl
palmitate in physiological conditions. Biochim. Biophys. Acta 2006, 1761, 4–10.
23. Rigtrup, K.M.; Kakkad, B.; Ong, D.E. Purification and partial characterization of a retinyl ester
hydrolase from the brush border of rat small intestine mucosa: Probable identity with brush
border phospholipase B. Biochemistry 1994, 33, 2661–2666.
24. Rigtrup, K.M.; Mcewen, L.R.; Said, H.M.; Ong, D.E. Retinyl ester hydrolytic activity associated
with human intestinal brush border membranes. Am. J. Clin. Nutr. 1994, 60, 111–116.
25. Rigtrup, K.M.; Ong, D.E. A retinyl ester hydrolase activity intrinsic to the brush border
membrane of rat small intestine. Biochemistry 1992, 31, 2920–2926.
26. Levin, G.; Mokady, S. Incorporation of all-trans- or 9-cis-beta-carotene into mixed micelles
in vitro. Lipids 1995, 30, 177–179.
27. Tyssandier, V.; Lyan, B.; Borel, P. Main factors governing the transfer of carotenoids from
emulsion lipid droplets to micelles. Biochim. Biophys. Acta 2001, 1533, 285–292.
28. Borel, P.; Armand, M.; Pasquier, B.; Senft, M.; Dutot, G.; Melin, C.; Lafont, H.; Lairon, D.
Digestion and absorption of tube-feeding emulsions with different droplet sizes and compositions
in the rat. J. Parenter. Enter. Nutr. 1994, 18, 534–543.
29. Bengtsson, A.; Larsson Alminger, M.; Svanberg, U. In vitro bioaccessibility of beta-carotene
from heat-processed orange-fleshed sweet potato. J. Agric. Food Chem. 2009, 57, 9693–9698.
30. Kirilenko, V.N.; Gregoriadis, G. Fat soluble vitamins in liposomes: Studies on incorporation
efficiency and bile salt induced vesicle disintegration. J. Drug Target. 1993, 1, 361–368.
Nutrients 2013, 5 3575
31. Noy, N.; Kelleher, D.J.; Scotto, A.W. Interactions of retinol with lipid bilayers: Studies with
vesicles of different radii. J. Lipid Res. 1995, 36, 375–382.
32. Perez, M.D.; Calvo, M. Interaction of b-lactoglobulin with retinol and fatty acids and its role as a
possible biological function for this protein: A review. J. Dairy Sci. 1995, 78, 978–988.
33. Said, H.M.; Ong, D.E.; Shingleton, J.L. Intestinal uptake of retinol: Enhancement by bovine milk
beta-lactoglobuline. Am. J. Clin. Nutr. 1989, 49, 690–694.
34. Godovac-Zimmermann, J. The Structural motif of B-Lactoglobulin and Retinol-Binding Protein:
A basic framework for binding and transport of small Hydrophobic molecules. Trends Biochem.
Sci. 1988, 13, 64–66.
35. Dufour, E.; Haertle, T. Binding of retinoids and beta-carotene to beta-lactoglobulin. Influence of
protein modifications. Biochim. Biophys. Acta 1991, 1079, 316–320.
36. Sivakumar, B.; Reddy, V. Absorption of labelled vitamin A in children during infection. Br. J.
Nutr. 1972, 27, 299–304.
37. O’neill, M.E.; Thurnham, D.I. Intestinal absorption of β-carotene, lycopene and lutein in men
and women following a standard meal: Response curves in the triacylglycerol-rich lipoprotein
fraction. Br. J. Nutr. 1998, 79, 149–159.
38. Novotny, J.A.; Dueker, S.R.; Zech, L.A.; Clifford, A.J. Compartmental analysis of the dynamics
of beta-carotene metabolism in an adult volunteer. J. Lipid Res. 1995, 36, 1825–1838.
39. Van Vliet, T.; Schreurs, W.H.; van Den Berg, H. Intestinal beta-carotene absorption and cleavage
in men: Response of beta-carotene and retinyl esters in the triglyceride-rich lipoprotein fraction
after a single oral dose of beta-carotene. Am. J. Clin. Nutr. 1995, 62, 110–116.
40. Faulks, R.M.; Hart, D.J.; Wilson, P.D.; Scott, K.J.; Southon, S. Absorption of all-trans and 9-cis
beta-carotene in human ileostomy volunteers. Clin. Sci. 1997, 93, 585–591.
41. Van Lieshout, M.; West, C.E.; van Breemen, R.B. Isotopic tracer techniques for studying the
bioavailability and bioefficacy of dietary carotenoids, particularly beta-carotene, in humans:
A review. Am. J. Clin. Nutr. 2003, 77, 12–28.
42. Van Loo-Bouwman, C.A.; Naber, T.H.; van Breemen, R.B.; Zhu, D.; Dicke, H.; Siebelink, E.;
Hulshof, P.J.; Russel, F.G.; Schaafsma, G.; West, C.E. Vitamin A equivalency and apparent
absorption of beta-carotene in ileostomy subjects using a dual-isotope dilution technique. Br. J.
Nutr. 2010, 103, 1836–1843.
43. Drevon, C.A. Absorption, transport and metabolism of vitamin E. Free Radic. Res. Commun.
1991, 14, 229–246.
44. Traber, M.G.; Sies, H. Vitamin E in humans: Demand and delivery. Annu. Rev. Nutr. 1996, 16,
45. Cohn, W. Bioavailability of vitamin E. Eur. J. Clin. Nutr. 1997, 51 (Suppl. 1), S80–S85.
46. Borel, P.; Lietz, G.; Goncalves, A.; Szabo De Edelenyi, F.; Lecompte, S.; Curtis, P.; Goumidi, L.;
Caslake, M.J.; Miles, E.A.; Packard, C.; et al. CD36 and SR-BI are involved in cellular uptake of
provitamin A carotenoids by Caco-2 and HEK cells, and some of their genetic variants are
associated with plasma concentrations of these micronutrients in humans. J. Nutr. 2013, 143,
47. During, A.; Harrison, E.H. Mechanisms of provitamin A (carotenoid) and vitamin A (retinol)
transport into and out of intestinal Caco-2 cells. J. Lipid Res. 2007, 48, 2283–2294.
Nutrients 2013, 5 3576
48. Quick, T.C.; Ong, D.E. Vitamin A metabolism in the human intestinal caco-2 cell line.
Biochemistry 1990, 29, 1116–1123.
49. Kawaguchi, R.; Yu, J.; Honda, J.; Hu, J.; Whitelegge, J.; Ping, P.; Wiita, P.; Bok, D.; Sun, H.
A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A. Science
2007, 315, 820–825.
50. Bouillet, P.; Sapin, V.; Chazaud, C.; Messaddeq, N.; Decimo, D.; Dolle, P.; Chambon, P.
Developmental expression pattern of Stra6, a retinoic acid-responsive gene encoding a new type
of membrane protein. Mech. Dev. 1997, 63, 173–186.
51. Isken, A.; Golczak, M.; Oberhauser, V.; Hunzelmann, S.; Driever, W.; Imanishi, Y.; Palczewski, K.;
von Lintig, J. RBP4 disrupts vitamin A uptake homeostasis in a STRA6-deficient animal model
for Matthew-Wood syndrome. Cell Metab. 2008, 7, 258–268.
52. Alapatt, P.; Guo, F.; Komanetsky, S.M.; Wang, S.; Cai, J.; Sargsyan, A.; Rodríguez Díaz, E.;
Bacon, B.T.; Aryal, P.; Graham, T.E. Liver retinol transporter and receptor for serum
retinol-binding protein (RBP4). J. Biol. Chem. 2013, 288, 1250–1265.
53. Borel, P.; Grolier, P.; Mekki, N.; Boirie, Y.; Rochette, Y.; Le Roy, B.; Alexandre-Gouabau, M.C.;
Lairon, D.; Azais-Braesco, V. Low and high responders to pharmacological doses of
beta-carotene: Proportion in the population, mechanisms involved and consequences on
beta-carotene metabolism. J. Lipid Res. 1998, 39, 2250–2260.
54. Jeanes, Y.M.; Hall, W.L.; Lodge, J.K. Comparative (2)H-labelled alpha-tocopherol biokinetics in
plasma, lipoproteins, erythrocytes, platelets and lymphocytes in normolipidaemic males. Br. J.
Nutr. 2005, 94, 92–99.
55. During, A.; Hussain, M.M.; Morel, D.W.; Harrison, E.H. Carotenoid uptake and secretion by
CaCo-2 cells: Beta-carotene isomer selectivity and carotenoid interactions. J. Lipid Res. 2002,
43, 1086–1095.
56. Reboul, E.; Thap, S.; Perrot, E.; Amiot, M.J.; Lairon, D.; Borel, P. Effect of the main dietary
antioxidants (carotenoids, gamma-tocopherol, polyphenols, and vitamin C) on alpha-tocopherol
absorption. Eur. J. Clin. Nutr. 2007, 61, 1167–1173.
57. Reboul, E.; Thap, S.; Tourniaire, F.; Andre, M.; Juhel, C.; Morange, S.; Amiot, M.J.; Lairon, D.;
Borel, P. Differential effect of dietary antioxidant classes (carotenoids, polyphenols, vitamin C
and vitamin E) on lutein absorption. Br. J. Nutr. 2007, 97, 440–446.
58. Hageman, S.H.; She, L.; Furr, H.C.; Clark, R.M. Excess vitamin E decreases canthaxanthin
absorption in the rat. Lipids 1999, 34, 627–631.
59. Kiefer, C.; Sumser, E.; Wernet, M.F.; von Lintig, J. A class B scavenger receptor mediates the
cellular uptake of carotenoids in Drosophila. Proc. Natl. Acad. Sci. USA 2002, 99, 10581–10586.
60. Lobo, M.V.; Huerta, L.; Ruiz-Velasco, N.; Teixeiro, E.; de La Cueva, P.; Celdran, A.;
Martín-Hidalgo, A.; Vega, M.A.; Bragado, R. Localization of the lipid receptors CD36 and
CLA-1/SR-BI in the human gastrointestinal tract: Towards the identification of receptors
mediating the intestinal absorption of dietary lipids. J. Histochem. Cytochem. 2001, 49,
61. Terpstra, V.; van Amersfoort, E.S.; van Velzen, A.G.; Kuiper, J.; van Berkel, T.J. Hepatic and
extrahepatic scavenger receptors: Function in relation to disease. Arterioscler. Thromb. Vasc.
Biol. 2000, 20, 1860–1872.
Nutrients 2013, 5 3577
62. Hauser, H.; Dyer, J.H.; Nandy, A.; Vega, M.A.; Werder, M.; Bieliauskaite, E.; Weber, F.E.;
Compassi, S.; Gemperli, A.; Boffelli, D.; et al. Identification of a receptor mediating absorption
of dietary cholesterol in the intestine. Biochemistry 1998, 37, 17843–17850.
63. Bietrix, F.; Yan, D.; Nauze, M.; Rolland, C.; Bertrand-Michel, J.; Comera, C.; Schaak, S.;
Barbaras, R.; Groen, A.K.; Perret, B.; et al. Accelerated lipid absorption in mice overexpressing
intestinal SR-BI. J. Biol. Chem. 2006, 281, 7214–7219.
64. Reboul, E.; Borel, P. Proteins involved in uptake, intracellular transport and basolateral secretion
of fat-soluble vitamins and carotenoids by mammalian enterocytes. Prog. Lipid Res. 2011, 50,
65. Reboul, E.; Abou, L.; Mikail, C.; Ghiringhelli, O.; Andre, M.; Portugal, H.; Jourdheuil-Rahmani, D.;
Amiot, MJ.; Lairon, D.; Borel, P. Lutein transport by Caco-2 TC-7 cells occurs partly by a
facilitated process involving the scavenger receptor class B type I (SR-BI). Biochem. J. 2005,
387, 455–461.
66. Van Bennekum, A.; Werder, M.; Thuahnai, S.T.; Han, C.H.; Duong, P.; Williams, D.L.;
Wettstein, P.; Schulthess, G.; Phillips, M.C. Class B scavenger receptor-mediated intestinal
absorption of dietary beta-carotene and cholesterol. Biochemistry 2005, 44, 4517–4525.
67. During, A.; Doraiswamy, S.; Harrison, E.H. Xanthophylls are preferentially taken up compared
with beta-carotene by retinal cells via a SRBI-dependent mechanism. J. Lipid Res. 2008, 49,
68. Moussa, M.; Landrier, J.F.; Reboul, E.; Ghiringhelli, O.; Comera, C.; Collet, X.; Fröhlich, K.;
Böhm, V.; Borel, P. Lycopene absorption in human intestinal cells and in mice involves
scavenger receptor class B type I but not Niemann-Pick C1-like 1. J. Nutr. 2008, 138,
69. Tandon, N.N.; Kralisz, U.; Jamieson, G.A. Identification of glycoprotein IV (CD36) as a primary
receptor for platelet-collagen adhesion. J. Biol. Chem. 1989, 264, 7576–7583.
70. Goudriaan, J.R.; Dahlmans, V.E.; Febbraio, M.; Teusink, B.; Romijn, J.A.; Havekes, L.M.;
Voshol, P.J. Intestinal lipid absorption is not affected in CD36 deficient mice. Mol. Cell.
Biochem. 2002, 239, 199–202.
71. Drover, V.A.; Ajmal, M.; Nassir, F.; Davidson, N.O.; Nauli, A.M.; Sahoo, D.; Tso, P.;
Abumrad, N.A. CD36 deficiency impairs intestinal lipid secretion and clearance of chylomicrons
from the blood. J. Clin. Investig. 2005, 115, 1290–1297.
72. Sakudoh, T.; Iizuka, T.; Narukawa, J.; Sezutsu, H.; Kobayashi, I.; Kuwazaki, S.; Banno, Y.;
Kitamura, A.; Sugiyama, H.; Takada, N.; et al. A CD36-related transmembrane protein is
coordinated with an intracellular lipid-binding protein in selective carotenoid transport for
cocoon coloration. J. Biol. Chem. 2010, 285, 7739–7751.
73. Moussa, M.; Gouranton, E.; Gleize, B.; Yazidi, C.E.; Niot, I.; Besnard, P.; Borel, P.; Landrier, J.F.
CD36 is involved in lycopene and lutein uptake by adipocytes and adipose tissue cultures.
Mol. Nutr. Food Res. 2011, 55, 578–584.
74. Ring, A.; Le Lay, S.; Pohl, J.; Verkade, P.; Stremmel, W. Caveolin-1 is required for fatty acid
translocase (FAT/CD36) localization and function at the plasma membrane of mouse embryonic
fibroblasts. Biochim. Biophys. Acta 2006, 1761, 416–423.
Nutrients 2013, 5 3578
75. Davies, J.P.; Levy, B.; Ioannou, Y.A. Evidence for a Niemann-pick C (NPC) gene family:
Identification and characterization of NPC1L1. Genomics 2000, 65, 137–145.
76. Altmann, S.W.; Davis, H.R., Jr.; Zhu, L.J.; Yao, X.; Hoos, L.M.; Tetzloff, G.; Iyer, S.P.;
Maguire, M.; Golovko, A.; Zeng, M.; et al. Niemann-Pick C1 Like 1 protein is critical for
intestinal cholesterol absorption. Science 2004, 303, 1201–1204.
77. Davies, J.P.; Scott, C.; Oishi, K.; Liapis, A.; Ioannou, Y.A. Inactivation of NPC1L1 causes
multiple lipid transport defects and protects against diet-induced hypercholesterolemia. J. Biol.
Chem. 2005, 280, 12710–12720.
78. Garcia-Calvo, M.; Lisnock, J.; Bull, H.G.; Hawes, B.E.; Burnett, D.A.; Braun, M.P.; Crona, J.H.;
Davis, H.R., Jr.; Dean, D.C.; Detmers, P.A.; et al. The target of ezetimibe is Niemann-Pick
C1-Like 1 (NPC1L1). Proc. Natl. Acad. Sci. USA 2005, 102, 8132–8137.
79. Duval, C.; Touche, V.; Tailleux, A.; Fruchart, J.C.; Fievet, C.; Clavey, V.; Staels, B.; Lestavel, S.
Niemann-Pick C1 like 1 gene expression is down-regulated by LXR activators in the intestine.
Biochem. Biophys. Res. Commun. 2006, 340, 1259–1263.
80. Davis, H.R., Jr.; Zhu, L.J.; Hoos, L.M.; Tetzloff, G.; Maguire, M.; Liu, J.; Yao, X.; Iyer, S.P.;
Lam, M.H.; Lund, E.G.; et al. Niemann-Pick C1 Like 1 (NPC1L1) is the intestinal phytosterol
and cholesterol transporter and a key modulator of whole-body cholesterol homeostasis. J. Biol.
Chem. 2004, 279, 33586–33592.
81. During, A.; Dawson, H.D.; Harrison, E.H. Carotenoid transport is decreased and expression of
the lipid transporters SR-BI, NPC1L1, and ABCA1 is downregulated in Caco-2 cells treated with
ezetimibe. J. Nutr. 2005, 135, 2305–2312.
82. Sato, Y.; Suzuki, R.; Kobayashi, M.; Itagaki, S.; Hirano, T.; Noda, T.; Mizuno, S.; Sugawara, M.;
Iseki, K. Involvement of cholesterol membrane transporter Niemann-Pick C1-like 1 in the
intestinal absorption of lutein. J. Pharm. Pharm. Sci. 2012, 15, 256–264.
83. Cai, L.; Eckhardt, E.R.; Shi, W.; Zhao, Z.; Nasser, M.; de Villiers, W.J.; van der Westhuyzen, D.R.
Scavenger receptor class B type I reduces cholesterol absorption in cultured enterocyte CaCo-2
cells. J. Lipid Res. 2004, 45, 253–262.
84. Reboul, E.; Goncalves, A.; Comera, C.; Bott, R.; Nowicki, M.; Landrier, J.F.;
Jourdheuil-Rahmani, D.; Dufour, C.; Collet, X.; Borel, P. Vitamin D intestinal absorption is not a
simple passive diffusion: Evidences for involvement of cholesterol transporters. Mol. Nutr. Food
Res. 2011, 55, 691–702.
85. Reboul, E.; Klein, A.; Bietrix, F.; Gleize, B.; Malezet-Desmoulins, C.; Schneider, M.; Margotat, A.;
Lagrost, L.; Collet, X.; Borel, P. Scavenger receptor class B type I (SR-BI) is involved in vitamin
E transport across the enterocyte. J. Biol. Chem. 2006, 281, 4739–4745.
86. Herron, K.L.; Mcgrane, M.M.; Waters, D.; Lofgren, I.E.; Clark, R.M.; Ordovas, J.M.;
Fernandez, M.L. The ABCG5 polymorphism contributes to individual responses to dietary
cholesterol and carotenoids in eggs. J. Nutr. 2006, 136, 1161–1165.
87. Harrison, E.H. Mechanisms of digestion and absorption of dietary vitamin A. Annu. Rev. Nutr.
2005, 25, 87–103.
Nutrients 2013, 5 3579
88. Batten, M.L.; Imanishi, Y.; Maeda, T.; Tu, D.C.; Moise, A.R.; Bronson, D.; Possin, D.;
Van Gelder, R.N.; Baehr, W.; Palczewski, K. Lecithin-retinol acyltransferase is essential for
accumulation of all-trans-retinyl esters in the eye and in the liver. J. Biol. Chem. 2004, 279,
89. Reboul, E.; Trompier, D.; Moussa, M.; Klein, A.; Landrier, J.F.; Chimini, G.; Borel, P.
ATP-binding cassette transporter A1 is significantly involved in the intestinal absorption of
alpha- and gamma-tocopherol but not in that of retinyl palmitate in mice. Am. J. Clin. Nutr. 2009,
89, 177–184.
90. Sauvant, P.; Mekki, N.; Charbonnier, M.; Portugal, H.; Lairon, D.; Borel, P. Amounts and types
of fatty acids in meals affect the pattern of retinoids secreted in human chylomicrons after a
high-dose preformed vitamin A intake. Metabolism 2003, 52, 514–519.
91. Amengual, J.; Golczak, M.; Palczewski, K.; von Lintig, J. Lecithin: Retinol acyltransferase is
critical for cellular uptake of vitamin A from serum retinol-binding protein. J. Biol. Chem. 2012,
287, 24216–24227.
92. Kawaguchi, R.; Zhong, M.; Kassai, M.; Ter-Stepanian, M.; Sun, H. STRA6-catalyzed vitamin A
influx, efflux, and exchange. J. Membr. Biol. 2012, 245, 731–745.
93. Castenmiller, J.J.M.; West, C.E. Bioavailability and bioconversion of carotenoids. Annu. Rev.
Nutr. 1998, 18, 19–38.
94. Lobo, G.P.; Amengual, J.; Palczewski, G.; Babino, D.; von Lintig, J. Carotenoid-oxygenases:
Key players for carotenoid function and homeostasis in mammalian biology. Biochim. Biophys.
Acta 2011, 1821, 78–81.
95. Bauernfeind, J.C. Carotenoid vitamin A precursors and analogs in foods and feeds. J. Agric.
Food Chem. 1972, 20, 456–473.
96. Van Vliet, T.; Vanschaik, F.; Schreurs, W.H.P.; van Den Berg, H. In vitro measurement of
beta-carotene cleavage activity: Methodological considerations and the effect of other
carotenoids on beta-carotene cleavage. Int. J. Vitam. Nutr. Res. 1996, 66, 77–85.
97. You, C.S.; Parker, R.S.; Goodman, K.J.; Swanson, J.E.; Corso, T.N. Evidence of cis-trans
isomerization of 9-cis-beta-carotene during absorption in humans. Am. J. Clin. Nutr. 1996, 64,
98. Noy, N. Retinoid-binding proteins: Mediators of retinoid action. Biochem. J. 2000, 348,
99. Napoli, J.L. Retinoic acid: Its biosynthesis and metabolism. Prog. Nucleic Acid Res. Mol. Biol.
1999, 63, 139–188.
100. Crow, J.A.; Ong, D.E. Cell-specific immunohistochemical localization of a cellular
retinol-binding protein (type two) in the small intestine of rat. Proc. Natl. Acad. Sci. USA 1985,
82, 4707–4711.
101. Suruga, K.; Suzuki, R.; Goda, T.; Takase, S. Unsaturated fatty acids regulate gene expression of
cellular retinol-binding protein, type II in rat jejunum. J. Nutr. 1995, 125, 2039–2044.
102. E, X.; Zhang, L.; Lu, J.; Tso, P.; Blaner, W.S.; Levin, M.S.; Li, E. Increased neonatal mortality
in mice lacking cellular retinol-binding protein II. J. Biol. Chem. 2002, 277, 36617–36623.
Nutrients 2013, 5 3580
103. Wongsiriroj, N.; Piantedosi, R.; Palczewski, K.; Goldberg, I.J.; Johnston, T.P.; Li, E.;
Blaner, W.S. The molecular basis of retinoid absorption: A genetic dissection. J. Biol. Chem.
2008, 283, 13510–13519.
104. Uchio, K.; Tuchweber, B.; Manabe, N.; Gabbiani, G.; Rosenbaum, J.; Desmouliere, A. Cellular
retinol-binding protein-1 expression and modulation during in vivo and in vitro myofibroblastic
differentiation of rat hepatic stellate cells and portal fibroblasts. Lab. Investig. 2002, 82, 619–628.
105. Tabunoki, H.; Sugiyama, H.; Tanaka, Y.; Fujii, H.; Banno, Y.; Jouni, Z.E.; Kobayashi, M.; Sato, R.;
Maekawa, H.; Tsuchida, K. Isolation, characterization, and cDNA sequence of a carotenoid
binding protein from the silk gland of Bombyx mori larvae. J. Biol. Chem. 2002, 277, 32133–32140.
106. Yu, L.; Bharadwaj, S.; Brown, J.M.; Ma, Y.; Du, W.; Davis, M.A.; Michaely, P.; Liu, P.;
Willingham, M.C.; Rudel, L.L. Cholesterol-regulated translocation of NPC1L1 to the cell surface
facilitates free cholesterol uptake. J. Biol. Chem. 2006, 281, 6616–6624.
107. Sane, A.T.; Sinnett, D.; Delvin, E.; Bendayan, M.; Marcil, V.; Menard, D.; Menard, D.;
Beaulieu, J.F.; Levy, E. Localization and role of NPC1L1 in cholesterol absorption in human
intestine. J. Lipid Res. 2006, 47, 2112–2120.
108. Pohl, J.; Ring, A.; Korkmaz, U.; Ehehalt, R.; Stremmel, W. FAT/CD36-mediated long-chain
fatty acid uptake in adipocytes requires plasma membrane rafts. Mol. Biol. Cell 2005, 16, 24–31.
109. Hansen, G.H.; Niels-Christiansen, L.L.; Immerdal, L.; Danielsen, E.M. Scavenger receptor class
B type I (SR-BI) in pig enterocytes: Trafficking from the brush border to lipid droplets during fat
absorption. Gut 2003, 52, 1424–1431.
110. Velkov, T.; Lim, M.L.; Horne, J.; Simpson, J.S.; Porter, C.J.; Scanlon, M.J. Characterization of
lipophilic drug binding to rat intestinal fatty acid binding protein. Mol. Cell. Biochem. 2009, 326,
111. Chuang, S.; Velkov, T.; Horne, J.; Porter, C.J.; Scanlon, M.J. Characterization of the drug
binding specificity of rat liver fatty acid binding protein. J. Med. Chem. 2008, 51, 3755–3764.
112. Besnard, P.; Niot, I.; Poirier, H.; Clement, L.; Bernard, A. New insights into the fatty
acid-binding protein (FABP) family in the small intestine. Mol. Cell. Biochem. 2002, 239,
113. Hanhoff, T.; Lucke, C.; Spener, F. Insights into binding of fatty acids by fatty acid binding
proteins. Mol. Cell. Biochem. 2002, 239, 45–54.
114. Borel, P.; Moussa, M.; Reboul, E.; Lyan, B.; Defoort, C.; Vincent-Baudry, S.; Maillot, M.;
Gastaldi, M.; Darmon, M.; Portugal, H.; et al. Human fasting plasma concentrations of vitamin E
and carotenoids, and their association with genetic variants in apo C-III, cholesteryl ester transfer
protein, hepatic lipase, intestinal fatty acid binding protein and microsomal triacylglycerol
transfer protein. Br. J. Nutr. 2009, 101, 680–687.
115. Nayak, N.; Harrison, E.H.; Hussain, M.M. Retinyl ester secretion by intestinal cells: A specific
and regulated process dependent on assembly and secretion of chylomicrons. J. Lipid Res. 2001,
42, 272–280.
116. Hussain, M.M.; Fatma, S.; Pan, X.; Iqbal, J. Intestinal lipoprotein assembly. Curr. Opin. Lipidol.
2005, 16, 281–285.
117. Huang, H.S.; Goodman, D.S. Intestinal absorbtion and metabolism of c-labeled viatamin a
alcohol and b-carotene in the rat. J. Biol. Chem. 1965, 240
, 2839–2844.
Nutrients 2013, 5 3581
118. Gouras, P.; Carr, R.E.; Gunkel, R.D. Retinitis pigmentosa in abetalipoproteinemia: Effects of
vitamin A. Investig. Ophthalmol. 1971, 10, 784–793.
119. Brunham, L.R.; Kruit, J.K.; Iqbal, J.; Fievet, C.; Timmins, J.M.; Pape, T.D.; Coburn, B.A.;
Bissada, N.; Staels, B.; Groen, A.K.; et al. Intestinal ABCA1 directly contributes to HDL
biogenesis in vivo. J. Clin. Investig. 2006, 116, 1052–1062.
120. Reboul, E.; Dyka, F.M.; Quazi, F.; Molday, R.S. Cholesterol transport via ABCA1: New insights
from solid-phase binding assay. Biochimie 2013, 95, 957–961.
121. Drobnik, W.; Lindenthal, B.; Lieser, B.; Ritter, M.; Weber, T.C.; Liebisch, G.; Giesa, U.; Igel, M.;
Borsukova, H.; Buchler, C.; et al. ATP-Binding Cassette transporter A1 (ABCA1) affects total
body sterol metabolism. Gastroenterology 2001, 120, 1203–1211.
122. Mulligan, J.D.; Flowers, M.T.; Tebon, A.; Bitgood, J.J.; Wellington, C.; Hayden, M.R.;
Attie, A.D. ABCA1 is essential for efficient basolateral cholesterol efflux during the absorption
of dietary cholesterol in chickens. J. Biol. Chem. 2003, 278, 13356–13366.
123. Nieland, T.J.; Chroni, A.; Fitzgerald, M.L.; Maliga, Z.; Zannis, V.I.; Kirchhausen, T.; Krieger, M.
Cross-inhibition of SR-BI- and ABCA1-mediated cholesterol transport by the small molecules
BLT-4 and glyburide. J. Lipid Res. 2004, 45, 1256–1265.
124. Lobo, G.P.; Hessel, S.; Eichinger, A.; Noy, N.; Moise, A.R.; Wyss, A.; Palczewski, K.;
von Lintig, J. ISX is a retinoic acid-sensitive gatekeeper that controls intestinal beta,beta-
carotene absorption and vitamin A production. FASEB J. 2010, 24, 1656–1666.
125. Levin, M.S.; Davis, A.E. Retinoic acid increases cellular retinol binding protein II mRNA and
retinol uptake in the human intestinal Caco-2 cell line. J. Nutr. 1997, 127, 13–17.
126. De Vogel-Van Den Bosch, H.M.; de Wit, N.J.; Hooiveld, G.J.; Vermeulen, H.; van Der Veen, J.N.;
Houten, S.M.; Kuipers, F.; Muller, M.; van der Meer, R. A cholesterol-free, high-fat diet
suppresses gene expression of cholesterol transporters in murine small intestine. Am. J. Physiol.
Gastrointest. Liver Physiol. 2008, 294, G1171–G1180.
127. Greenwalt, D.E.; Scheck, S.H.; Rhinehart-Jones, T. Heart CD36 expression is increased in
murine models of diabetes and in mice fed a high fat diet. J. Clin. Investig. 1995, 96, 1382–1388.
128. Spady, D.K.; Kearney, D.M.; Hobb, H.H. Polyunsaturated fatty acids up-regulate hepatic
scavenger receptor B1 (SR-BI) expression and HDL cholesteryl ester uptake in the hamster.
J. Lipid Res. 1999, 40, 1384–1394.
129. Borel, P.; Moussa, M.; Reboul, E.; Lyan, B.; Defoort, C.; Vincent-Baudry, S.; Maillot, M.;
Gastaldi, M.; Darmon, M.; Portugal, H.; et al. Human plasma levels of vitamin E and carotenoids
are associated with genetic polymorphisms in genes involved in lipid metabolism. J. Nutr. 2007,
137, 2653–2659.
130. Borel, P.; de Edelenyi, F.S.; Vincent-Baudry, S.; Malezet-Desmoulin, C.; Margotat, A.; Lyan, B.;
Gorrand, J.M.; Meunier, N.; Drouault-Holowacz, S.; Bieuvelet, S. Genetic variants in BCMO1
and CD36 are associated with plasma lutein concentrations and macular pigment optical density
in humans. Ann. Med. 2010, 43, 47–59.
© 2013 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
... depending on the passive transport by the cell uptake assay [11]. Moreover, Reboul veri ed that lutein was mainly passively absorbed [12]. Currently, there is limited information on the detailed transport mechanism of micelle-carrying lutein in epithelial cells. ...
... After micellar treatment, the bidirectional penetration ratio of lutein decreased to close to 0.5, suggesting that the transport of micellar lutein in the cell is mainly passive diffusion, but there are other transport pathways. Therefore, the main permeation mechanism of lutein micelle and lutein is passive transport with other transport pathways [12,23]. ...
Full-text available
Background: Micellization can significantly promote the absorption of lutein. However, the mechanism is still unknown. Methods and Results: This study investigated the effect of micellar treatment on lutein absorption and transmembrane transport mechanism by in vitro digestion and the Caco-2 cell model. The results showed that the bioaccessibility of micellized lutein was 1.42 times that of lutein. The Apparent Permeability Coefficients (Papp) indicated that the main transmembrane pathway was found as passive transport. While solubility is regarded as a restrictive factor for lutein absorption. Further, nystatin and dynasore dramatically decreased the absorption of lutein micelle. In addition, micellization treatment increased cluster determinant 36 (CD36) expression (p<0.05). And lutein micelle treatments significantly lower SCARB1, SREBF, and ABCA1 mRNA expression and increased the CD36 mRNA expression (p<0.05). Conclusions: This study demonstrated that micellization significantly improved the absorption of lutein. The transmembrane absorption pathway in intestinal cells was mainly passive transport, as well as clathrin-mediated and caveolin/lipoprotein-mediated endocytosis.
... These then travel into the enterocyte of the small intestine and are absorbed by a passive, non-saturable mechanism. Carotenoids are then packaged in chylomicrons and move, via the lymph, to the liver [57]. It has been agreed that the extent of β-carotene absorption by intestinal enterocytes is species dependent; humans, for example, absorb significant amounts of intact β-carotene compared to rodents [58]. ...
Full-text available
Citation: Darwish, R.M.; Magee, K.J.; Gedi, M.A.; Farmanfarmaian, A.; Zaky, A.S.; Young, I.; Gray, D.A. Abstract: Currently, there is an urgent need for the growing aquaculture sector to rely on sustainable ingredients which can achieve optimal growth while maintaining fish's nutritional value (especially omega-3 fatty acid content) for human consumption. Here, C. reinhardtii biomass was substituted for fishmeal in zebrafish (Danio rerio) diets in wild-type and mutant (Casper) strains. Four isonitrogenous (46% cp), isocaloric (19-21 MJ/kg DW) diets were prepared with C. reinhardtii replacing 10% (C10), 20% (C20), and 50% (C50) of the fishmeal component of the diet formulation. Over 8 weeks of feeding trials, the zebrafish showed a significant growth improvement when fed C10, C20, and C50 compared with the control (no C. reinhardtii), with C20 giving the best performance in terms of growth, feed conversion ratio (FCR), and specific growth rate (SGR). Interestingly, C. reinhardtii in the diet increased the levels of linolenic acid (C18:3 n-3) and hexadecatrienoic acid (C16: 4-n-3) (p ≤ 0.05) in the zebrafish. Yellow pigmentation, which was shown to be lutein, was observed in eggs and zebrafish flesh for fish fed a diet containing C. reinhardtii. Moreover, the zebrafish assimilated β-carotene from C. reinhardtii and converted it to vitamin A. Overall, while replacing 20% of fishmen in the zebrafish's diet with C. reinhardtii biomass offers the best results, replacement with only 10% showed a significant benefit for the zebrafish. Furthermore, replacing fishmeal with 50% C. reinhardtii is still possible and beneficial, and C. reinhardtii whole cells are digestible by zebrafish, thus demonstrating that C. reinhardtii not only has the potential to serve as a feed supplement but that it can also act as a feed substitute once the production cost of microalgae becomes competitive.
... incorporated into micelles 22 and absorbed with fat in the upper half of the small intestine. 23 Factors such as the bioavailability of lipids to be emulsified into micelles can impact the time it takes for the fat to be absorbed 21 and, subsequently, the time to absorb fat-soluble vitamins. Sampling before the animal eats helps ensure that there is no spike of nutrients traveling through the blood at the time the sample is taken, although this may result in reporting of lower levels of nutrients. ...
Objective: Determine how sample handling affects nutrient analysis of fat-soluble vitamins and minerals. Materials and methods: In experiment 1, blood was collected in either plasma or serum blood tubes and exposed to 4 hours of light or wrapped in aluminum foil to protect from light. In experiment 2, blood was collected at hours 0, 1, 2, 3, 4, 6, and 12 after the consumption of feed. In experiment 3, vitamins and minerals were assessed in varying degrees of hemolyzed blood samples. Experiment 4 evaluated liver samples exposed to various temperatures for up to 12 hours. In experiment 5, serum and liver samples were processed the day of, 1 day after, or 2 days after collection and subsequent placement into coolers with icepacks. Results: There was a significant difference (P < .05) for the interaction of tube type and light exposure for vitamin D (25-hydroxyvitamin D3) and a tendency (P < .10) for a tube type and light exposure interaction for vitamin A (retinol). Experiment 2 found serum vitamin concentrations changed post feed consumption both linearly and quadratically. Alpha-tocopherol peaked at 4 hours post meal consumption, whereas retinol peaked at 6 hours. In experiment 3, the degree of hemolysis affected (P < .05) nutrient concentration. Experiment 4 and 5 showed no differences (P > .05) in degradation of retinol and alpha-tocopherol. Implication: As many pre-analytical factors can affect laboratory results, care must be taken when collecting, handling, and storing samples for diagnostic analysis of vitamins and minerals.
Full-text available
Background: Non-alcoholic fatty liver disease (NAFLD) has become an urgent public health issue with high global prevalence, but data on NAFLD are inconsistent. The association of dietary retinol intake with the NAFLD risk was not well documented in previous studies. Aims: To explore the relationship between dietary retinol intake from different sources and NAFLD risk among American adults. Methods: Data were collected from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2014. Logistic regression and restricted cubic spline models were used to estimate the relationship between dietary retinol intake and NAFLD risk. Results: 6,613 adult participants were included. After adjusting potential confounders, the odds ratios (ORs) with 95% confidence intervals (CIs) of NAFLD for the highest quartile intake of total, animal-derived, plant-derived dietary retinol, were respectively 0.86 (0.69-1.06), 0.97 (0.74-1.28), and 0.78 (0.61-0.99), compared to the lowest quartile. Stratifying gender and age, plant-derived dietary retinol was inversely associated with NAFLD risk in females and participants aged <45 years. Dose-response analysis indicated a linear negative relationship between plant-derived dietary retinol intake and NAFLD risk. Conclusion: Consumption of plant-derived retinol was protective against NAFLD, especially in women and those aged <45 years among adult American.
Full-text available
One hundred and fifty-two nursery pigs (PIC, Hendersonville, TN) were randomly assigned to mix sex pens and one of six dietary treatments in a 3 × 2 factorial. Diets included no added fat, 3% added choice white grease, or 3% added soy oil with either a supplemented vitamin A (for a total of 11,640 IU vitamin A/kg, Rovimix A 1000, DSM, Parsippany, NJ, US) or beta-carotene (for a total of 8,708 IU vitamin A/kg equivalent, Rovimix β-Carotene 10%, DSM). Pigs were given a 3-d adaptation period upon arrival. Pigs were weighed at the start of the study and at the end of each phase. A blood sample was taken from one pig per pen at the start and end of the study. Tissues were collected from eight pigs at the start of the study and six pigs per treatment at the end of the study. Data were analyzed via the GLIMMIX procedure in SAS 9.4 (SAS Inst., Cary, NC). Pen was the experimental unit, and repeated measures were used for growth performance and blood parameters. There was no fat by supplement interaction (P > 0.05) on body weight (BW), but there was a tendency (P = 0.054) for heavier BWs when soy oil was added to diets. There was no difference (P > 0.05) in average daily feed intake or average daily gain (ADG). There was an improved gain:feed (P = 0.02) when pigs were fed choice white grease over no added fat. There were time differences (P < 0.05) for plasma vitamins A (retinol), D (25 hydroxy vitamin D3), and E (alpha-tocopherol). Vitamin A and D values were higher at the end of the study, whereas vitamin E values were lower at the end of the study. The choice white grease diets had the highest (P < 0.05) plasma vitamins D and E (6.74 ng/mL and 2.87 ppm, respectively). Pigs supplemented with vitamin A had higher (P < 0.05) hepatic vitamin A than pigs supplemented with beta-carotene (19.9 vs. 15.6 ppm, respectively). There were no differences (P < 0.05) between immunoglobulins G and M or mRNA abundance of select genes (retinol binding protein 2, alcohol dehydrogenase class 1, lecithin retinol acyltransferase phosphatidylcholine-retinol O-acyltransferase, and beta-carotene oxygenase 1). In conclusion, fat inclusion level and type, with either vitamin A or beta-carotene supplementation, did not affect the overall nursery pig growth performance. The addition of fat resulted in an increase in ADG and BW. Diets with choice white grease had the highest plasma vitamins D and E, and supplemental vitamin A increased hepatic vitamin A.
Vitamins are essential components of enzyme systems involved in normal growth and function. The quantitative estimation of the proportion of dietary vitamins, that is in a form available for utilization by the human body, is limited and fragmentary. This review provides the current state of knowledge on the bioavailability of thirteen vitamins and choline, to evaluate whether there are differences in vitamin bioavailability when human foods are sourced from animals or plants. The bioavailability of naturally occurring choline, vitamin D, vitamin E, and vitamin K in food awaits further studies. Animal-sourced foods are the almost exclusive natural sources of dietary vitamin B-12 (65% bioavailable) and preformed vitamin A retinol (74% bioavailable), and contain highly bioavailable biotin (89%), folate (67%), niacin (67%), pantothenic acid (80%), riboflavin (61%), thiamin (82%), and vitamin B-6 (83%). Plant-based foods are the main natural sources of vitamin C (76% bioavailable), provitamin A carotenoid β-carotene (15.6% bioavailable), riboflavin (65% bioavailable), thiamin (81% bioavailable), and vitamin K (16.5% bioavailable). The overview of studies showed that in general, vitamins in foods originating from animals are more bioavailable than vitamins in foods sourced from plants.
Vitamins are substances necessary to sustain life, with many functions. Vitamins must be obtained from food, as they are either not made in the body at all or are not made in sufficient quantities for growth, vitality and wellbeing. Lack of a particular vitamin can lead to incomplete metabolism, fatigue and other important health problems. Deficiency of a vitamin causes symptoms which can be cured by that vitamin. Large doses of vitamins may slow or ever reverse diseases such as cancer, osteoporosis, nerve degeneration and heart disease.
Full-text available
Metabolism of a 73 mumol oral dose of beta-carotene-d8 in olive oil was determined from plasma beta-carotene-d8 and retinol-d4 concentration-time curves in an adult male. beta-Carotene-d8 and retinol-d4 concentrations in serial plasma were measured using high performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS), respectively. Plasma beta-carotene-d8 and retinol-d4 concentration-time curves were described by a 5-term and a 3-term polyexponential equation, respectively, using an empirical description of beta-carotene metabolism. A physiologic compartmental model of beta-carotene metabolism was also constructed and tested. This model suggests that 22% of the beta-carotene dose is absorbed: 17.8% as intact beta-carotene and 4.2% as retinoid. Also, it suggests that both liver and enterocyte are important in converting beta-carotene to retinoid; 43% is converted in liver and 57% in enterocyte. Finally, it suggests that the mean residence time for beta-carotene is 51 days and that the 73 mumole dose does not alter the fractional transfer coefficients of the system after absorption takes place. The issue of central versus eccentric cleavage of beta-carotene in humans can be studied with further modeling combined with use of appropriately labeled beta-carotene.
Full-text available
Background: The aim of this study was to quantitatively evaluate the relative contributions to in vivo lipolysis of gastric and pancreatic lipases. Methods: Gastric and pancreatic lipase secretions were measured, and their respective levels were determined in duodenal fluid during the digestion of a liquid test meal in healthy volunteers. Gastric lipase activity was clearly distinguished from that of pancreatic lipase by using both a specific enzymatic assay and an enzyme-linked immunosorbent assay. Lipolysis products were monitored throughout the digestion period. Results: On a weight basis, the ratio of pancreatic lipase to gastric lipase total secretory outputs was found to be around four after 3 hours of digestion. The level of gastric hydrolysis was calculated to be 10% +/- 1% of the acyl chains released from the meal triglycerides. Gastric lipase remained active in the duodenum where it might still hydrolyze 7.5% of the triglyceride acyl chains. Conclusions: Globally during the whole digestion period, gastric lipase might hydrolyze 17.5% of the triglyceride acyl chains. In other words, gastric lipase might hydrolyze 1 acyl chain of 4, which need to be hydrolyzed for a complete intestinal absorption of monoglycerides and free fatty acids resulting from the degradation of two triglyceride molecules.
Full-text available
Active vitamin A metabolites, known as retinoids, are essential for multiple physiological processes, ranging from vision to embryonic development. These small hydrophobic compounds associate in vivo with soluble proteins that are present in a variety of cells and in particular extracellular compartments, and which bind different types of retinoids with high selectivity and affinity. Traditionally, retinoid-binding proteins were viewed as transport proteins that act by solubilizing and protecting their labile ligands in aqueous spaces. It is becoming increasingly clear, however, that, in addition to this general role, retinoid-binding proteins have diverse and specific functions in regulating the disposition, metabolism and activities of retinoids. Some retinoid-binding proteins appear to act by sequestering their ligands, thereby generating concentration gradients that allow cells to take up retinoids from extracellular pools and metabolic steps to proceed in energetically unfavourable directions. Other retinoid-binding proteins regulate the metabolic fates of their ligands by protecting them from some enzymes while allowing metabolism by others. In these cases, delivery of a bound retinoid from the binding protein to the 'correct' enzyme is likely to be mediated by direct and specific interactions between the two proteins. One retinoid-binding protein was reported to enhance the ability of its ligand to regulate gene transcription by directly delivering this retinoid to the transcription factor that is activated by it. 'Channelling' of retinoids between their corresponding binding protein and a particular protein target thus seems to be a general theme through which some retinoid-binding proteins exert their effects.
Full-text available
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 β-carotene (β-C) were curvilinear, time-dependent (2–16 h), saturable, and concentration-dependent (apparent Km of 7–10 μM) processes. Under linear concentration conditions at 16 h incubation, the extent of absorption of all-trans β-C was 11% (80% in chylomicrons), while those of 9-cis- and 13-cis-β-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 α-carotene (α-C), lutein (LUT), and lycopene (LYC) in CaCo-2 cells were 10%, 7%, and 2.5%, respectively. Marked carotenoid interactions were observed between LYC/β-C and β-C/α-C. The present results indicate that β-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 β-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.
Full-text available
A high intake of fruit and vegetables is believed to be protective against heart disease and cancer. β-Carotene has been closely examined for evidence of these protective properties but evidence is still conflicting and there are many other carotenoids in plant foods which deserve attention. This paper reports studies on the concentrations of lutein and lycopene in the triacylglycerol-rich lipoprotein (TRL) fraction of plasma in comparison with β-carotene following a large dose of the respective carotenoids fed with a standard meal after an overnight fast. β-Carotene (40 mg) was given to twelve volunteers (six men and six women) and six of the same volunteers (three men and three women) also received 31·2mg lutein or 38 mg lycopene. Plasma was collected at hourly intervals for 8 h and the TRL fraction was separated and subsequently analysed for the respective carotenoids and retinyl palmitate in the case of β-carotene. Intestinal uptake of the three carotenoids was estimated using the ‘area under the curve’ method and apparent absorption was calculated from these results. The response curves in the TRL fraction for β-carotene and retinyl palmitate occurred maximally over the fourth to fifth hour postprandially. There was a correlation between the TRL concentrations of β-carotene and retinyl palmitate (males r 0·62, P < 0·001; females r 0·52, P < 0·001) and there was no significant difference between men and women either in the total amount of β-carotene appearing in the TRL fraction or in the amount converted to retinol. On estimation, approximately l·4 mg of the 40 mg β-carotene dose was absorbed and this was not significantly different from the amount of lycopene (l·0 mg) but significantly different (P < 0·05) from the amount of lutein (0·8 mg) absorbed, after correction for the smaller doses administered. There was approximately a twofold difference between subjects in the uptake of β-carotene into the TRL fraction, a two- to threefold variation in lycopene and a two- to threefold variation in lutein. Despite these inter-subject differences, in three volunteers between whom there was a threefold difference in β-carotene in the TRL fraction and a twofold difference in retinol formation, repeat experiments with β-carotene 4 months later found differences of only 3–6 % in the TRL β-carotene content and 4–9% for the TRL retinol formed. In conclusion, large inter-subject variation in TRL carotene uptake precluded any differences between sexes but surprising intra-subject consistency was observed in TRL β-carotene uptake of three subjects.
Full-text available
Various studies suggest thatall-trans- and 9-cis-β-carotene are absorbed in the intestine to different extents. The present study was undertaken to evaluate the degree ofin vitro incorporation of the two isomers into intestinal mixed micelles, which is an essential early step in the absorption process. The micelles were designed to simulate those present during fat digestion in the lumen of the human small intestine with respect to bile salts, lipids, pH and temperature. Solutions ofall-trans-and 9-cis-β-carotene at various ratios were added to the lipid mixture. A direct correlation was seen between the 9-cis-β-carotene level in the mixture and the degree of total β-carotene incorporation into micelles. An increased level ofall-trans-β-carotene incorporated into the micelles. In contrast, when carotene mixtures enriched with the 9-cis isomer were used, an increase in the level of total carotene in the solution was accompanied by a constant or even enhanced carotene incorporation. The results indicate that the differences in the absorption of β-carotene isomers might be the result of their different ability to be incorporated into the lipid micelles of the intestinal lumen. In addition, the results point toward the possibility that ingestion of 9-cis-β-carotene by humans may increase carotene availability.
Full-text available
Scavenger receptor class B type I (SR-BI) and cluster determinant 36 (CD36) have been involved in cellular uptake of some provitamin A carotenoids. However, data are incomplete (e.g., there are no data on α-carotene), and it is not known whether genetic variants in their encoding genes can affect provitamin A carotenoid status. The objectives were 1) to assess the involvement of these scavenger receptors in cellular uptake of the main provitamin A carotenoids (i.e., β-carotene, α-carotene, and β-cryptoxanthin) as well as that of preformed vitamin A (i.e., retinol) and 2) to investigate the contribution of genetic variations in genes encoding these proteins to interindividual variations in plasma concentrations of provitamin A carotenoids. The involvement of SR-BI and CD36 in carotenoids and retinol cellular uptake was investigated in Caco-2 and human embryonic kidney (HEK) cell lines. The involvement of scavenger receptor class B type I (SCARB1) and CD36 genetic variants on plasma concentrations of provitamin A carotenoids was assessed by association studies in 3 independent populations. Cell experiments suggested the involvement of both proteins in cellular uptake of provitamin A carotenoids but not in that of retinol. Association studies showed that several plasma provitamin A carotenoid concentrations were significantly different (P < 0.0083) between participants who bore different genotypes at single nucleotide polymorphisms and haplotypes in CD36 and SCARB1. In conclusion, SR-BI and CD36 are involved in cellular uptake of provitamin A carotenoids, and genetic variations in their encoding genes may modulate plasma concentrations of provitamin A carotenoids at a population level.
Full-text available
Vitamin A (retinol) is absorbed in the small intestine, stored in liver, and secreted into circulation bound to serum retinol-binding protein (RBP4). Circulating retinol may be taken up by extrahepatic tissues or recycled back to liver multiple times before it is finally metabolized or degraded. Liver exhibits high affinity binding sites for RBP4, but specific receptors have not been identified. The only known high affinity receptor for RBP4, Stra6, is not expressed in the liver. Here we report discovery of RBP4 receptor-2 (RBPR2), a novel retinol transporter expressed primarily in liver and intestine and induced in adipose tissue of obese mice. RBPR2 is structurally related to Stra6 and highly conserved in vertebrates, including humans. Expression of RBPR2 in cultured cells confers high affinity RBP4 binding and retinol transport, and RBPR2 knockdown reduces RBP4 binding/retinol transport. RBPR2 expression is suppressed by retinol and retinoic acid and correlates inversely with liver retinol stores in vivo. We conclude that RBPR2 is a novel retinol transporter that potentially regulates retinol homeostasis in liver and other tissues. In addition, expression of RBPR2 in liver and fat suggests a possible role in mediating established metabolic actions of RBP4 in those tissues.
The kinetics of the bovine cholesterol esterase-catalyzed hydrolysis of three stereoisomers of α-tocopheryl acetate (αT-Ac) have been examined in vitro at 37°C in the presence of dimyristoylphosphatidylcholine and sodium cholate. In contrast to in vivo results obtained earlier in rats (Ingold, K.U., Burton, G.W., Foster, D.O., Hughes, L., Lindsay, D.A. and Webb, A. (1987) Lipids 22, 163–172), 2R,4'R,8'R-αT-Ac (RRR-αT-Ac) is hydrolyzed (to form “natural” vitamin E) more slowly (by a factor of approx. 7) than SRR-(and SSS-αT-Ac. It is concluded that chirality at position 2 plays the dominant role in determining Vmax . The Kn values show that RRR-αT-Ac is 2.1- and 2.7-times more strongly bound to the enzyme than are the SRR- and SSS-αT-Ac, respectively. The reaction is subject to competitive inhibition by the product with RRR-aT being 2.3-times as powerful an inhibitor as SRR--αT.
It is now well established that the ATP-binding cassette transporter A1 (ABCA1) plays a pivotal role in HDL metabolism, reverse cholesterol transport and net efflux of cellular cholesterol and phospholipids. We aimed to resolve some uncertainties related to the putative function of ABCA1 as a mediator of lipid transport by using a methodology developed in the laboratory to isolate a protein and study its interactions with other compounds. ABCA1 was tagged with the 1D4 peptide at the C terminus and expressed in human HEK 293 cells. Preliminary experiments showed that the tag modified neither the protein expression/ localization within the cells nor the ability of ABCA1 to promote cholesterol cellular efflux to apolipoprotein A-I. ABCA1-1D4 was then purified and reconstituted in liposomes. ABCA1 displayed an ATPase activity in phospholipid liposomes that was significantly decreased by cholesterol. Finally, interactions with either cholesterol or apolipoprotein A-I were assessed by binding experiments with protein immobilized on an immunoaffinity matrix. Solid-phase binding assays showed no direct binding of cholesterol or apolipoprotein A-I to ABCA1. Overall, our data support the hypothesis that ABCA1 is able to mediate the transport of cholesterol from cells without direct interaction and that apo A-I primarily binds to membrane surface or accessory protein(s).