Am J Physiol Endocrinol Metab 296: E1183–E1194, 2009.
First published January 21, 2009; doi:10.1152/ajpendo.90899.2008.
Review
Intestinal lipid absorption
Jahangir Iqbal and M. Mahmood Hussain
Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York
Submitted 7 November 2008; accepted in final form 19 January 2009
intestine; dietary fat; triacylglycerol; cholesterol; phospholipids; fat-soluble vitamins; microsomal triglyceride transfer protein
DIETARY FATS CONSIST OF A WIDE ARRAY of polar and nonpolar
lipids (32, 33). Triacylglycerol (TAG) is the dominant fat in the
diet, contributing 90 –95% of the total energy derived from
dietary fat. Dietary fats also include phospholipids (PLs),
sterols (e.g., cholesterol), and many other lipids (e.g., fatsoluble vitamins). The predominant PL in the intestinal lumen
is phosphatidylcholine (PC), which is derived mostly from bile
(10 –20 g/day in humans) but also from the diet (⬃1–2 g/day).
The predominant dietary sterols are cholesterol (mostly of
animal origin) and ␤-sitosterol (the major plant sterol). Although ␤-sitosterol accounts for 25% of dietary sterols, it is not
absorbed by humans under physiological conditions.
Researchers have been investigating the various steps involved in lipid digestion, absorption, and metabolism to identify factors that could serve as targets for the development of
drugs capable of reducing the risk of lipid-associated disorders,
including dyslipidemias and cardiovascular disease. In so doing, they have explored key aspects of lipid digestion hydrolysis, emulsification, and micelle formation. They have also
explored key issues of absorption, e.g., the uptake of the
products of lipid hydrolysis by enterocytes (the epithelial cells
lining the walls of the intestinal lumen) and their transport to
intracellular compartments, where fatty acids and sterols are
transformed into neutral lipids. Efficient absorption ensures
Address for reprint requests and other correspondence: J. Iqbal or M. M.
Hussain, Dept. of Anatomy and Cell Biology, 450 Clarkson Ave., State
University of New York Downstate Medical Center, Brooklyn, NY 11203
(e-mail: [email protected] or [email protected]).
http://www.ajpendo.org
that dietary fat is available to be used as a source of energy that
supports various cellular functions or to be stored and serve as
reservoirs for lipoprotein trafficking, bile acid synthesis, steroidogenesis, membrane formation and maintenance, and epidermal integrity in various mammalian cells. Excess fat is
stored in cytosolic lipid droplets until it is needed to support
intracellular processes.
In this review, we will concentrate on the biochemical
processes involved in the digestion and absorption of the most
common dietary lipids: TAGs, PLs, cholesterol, and fat-soluble
vitamins.
DIGESTION AND ABSORPTION OF LIPIDS:
A BRIEF OVERVIEW
The digestion of lipids begins in the oral cavity through
exposure to lingual lipases, which are secreted by glands in the
tongue to begin the process of digesting triglycerides. Digestion continues in the stomach through the effects of both
lingual and gastric enzymes. The stomach is also the major site
for the emulsification of dietary fat and fat-soluble vitamins,
with peristalsis a major contributing factor. Crude emulsions of
lipids enter the duodenum as fine lipid droplets and then mix
with bile and pancreatic juice to undergo marked changes in
chemical and physical form. Emulsification continues in the
duodenum along with hydrolysis and micellization in preparation for absorption across the intestinal wall. (For details about
the emulsification, hydrolysis, and micellization of fats, see
Refs. 131 and 144.)
0193-1849/09 $8.00 Copyright © 2009 the American Physiological Society
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Iqbal J, Hussain MM. Intestinal lipid absorption. Am J Physiol Endocrinol Metab 296: E1183–E1194, 2009. First published January 21, 2009;
doi:10.1152/ajpendo.90899.2008.—Our knowledge of the uptake and transport
of dietary fat and fat-soluble vitamins has advanced considerably. Researchers have
identified several new mechanisms by which lipids are taken up by enterocytes and
packaged as chylomicrons for export into the lymphatic system or clarified the
actions of mechanisms previously known to participate in these processes. Fatty
acids are taken up by enterocytes involving protein-mediated as well as proteinindependent processes. Net cholesterol uptake depends on the competing activities
of NPC1L1, ABCG5, and ABCG8 present in the apical membrane. We have considerably more detailed information about the uptake of products of lipid hydrolysis, the
active transport systems by which they reach the endoplasmic reticulum, the mechanisms by which they are resynthesized into neutral lipids and utilized within the
endoplasmic reticulum to form lipoproteins, and the mechanisms by which lipoproteins
are secreted from the basolateral side of the enterocyte. apoB and MTP are known to
be central to the efficient assembly and secretion of lipoproteins. In recent studies,
investigators found that cholesterol, phospholipids, and vitamin E can also be secreted
from enterocytes as components of high-density apoB-free/apoAI-containing lipoproteins. Several of these advances will probably be investigated further for their potential
as targets for the development of drugs that can suppress cholesterol absorption, thereby
reducing the risk of hypercholesterolemia and cardiovascular disease.
Review
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INTESTINAL LIPID ABSORPTION
Triacylglycerides
Digestion and absorption of TAGs. TAG is digested primarily by pancreatic lipase in the upper segment of the jejunum.
This process generates a liquid-crystalline interface at the
surface of the emulsion particles (13, 161). The activity of
pancreatic lipase on the sn-1 and sn-3 positions of the TAG
molecule results in the release of 2-monoacylglycerol (2MAG) and free fatty acids (FFAs) (122–124); 2-MAG is the
predominant form in which MAG is absorbed from the small
intestine. The formation of 2-MAG (and 1-MAG) through
isomerization in an aqueous medium occurs more slowly than
the uptake of 2-MAG from the small intestine (20). Further
hydrolysis of 1- or 2-MAG by pancreatic lipase results in the
formation of glycerol and FFAs (78); cholesterol esterase can
also hydrolyze the acyl group at the sn-2 position to form
glycerol and FFAs (111).
Free fatty acids are taken up from the intestinal lumen into
the enterocytes and used for the biosynthesis of neutral fats. A
protein-independent diffusion model and protein-dependent
mechanisms have been proposed for the uptake and transport
of fatty acids (FAs) across the apical membrane of the enterocyte (for details, see Ref. 119). A number of candidate proteins
have been proposed to take part in protein-dependent uptake
mechanisms. FAT/CD36 plays a key role in the uptake of FAs
(1, 19). FAT/CD36 is highly expressed in the intestine (37),
and its expression is upregulated by the presence of dietary fat
(148), genetic obesity, and diabetes mellitus (64). Studies in
CD36-null mice suggest that it is intimately involved in the
uptake and transport of FAs targeted for transport to the
lymphatic system through their use in the assembly of chylomicrons (45). This relationship is suggested by the finding that
the uptake of FAs is not impaired in CD36-null animals.
However, lipids tend to accumulate in the proximal small
intestine of these animals primarily because of decreased
transport of FAs to the lymphatic system (45). FA transport
AJP-Endocrinol Metab • VOL
proteins (FATPs) are well represented in the small intestine by
their FATP4 isoform, which is thought to help facilitate the
uptake of FAs by the enterocytes (162).
TAG synthesis. Once inside the enterocyte, the products of
TAG hydrolysis must traverse the cytoplasm to reach the
endoplasmic reticulum (ER), where they are used to synthesize
complex lipids. Specific binding proteins carry FAs and MAG
to the intracellular site, where they will be used for TAG
biosynthesis. The two major fatty acid-binding proteins
(FABPs) found in enterocytes are liver FABP and intestinal
FABP (2, 16, 69). Most TAG biosynthesis in the enterocyte
occurs along the MAG pathway, in which MAG and fatty
acyl-CoA are covalently joined to form diacylglycerol (DAG)
in a reaction catalyzed by monoacylglycerol acyltransferases
(MGATs) (40, 197). Further acylation of DAG by diacylglycerol
acyltransferase (DGAT) leads to the synthesis of TAG. Two
DGATs have been identified and characterized: DGAT1 and
DGAT2. [For additional information about DGATs, refer to
the recent review (197).] DGAT2 is expressed mainly in the
liver and intestine. Its importance in the absorption of fat has
been demonstrated by a reduction in fat absorption in DGAT2knockout (KO) animals. DGAT1, which is expressed in several
tissues (including liver, intestine, and skin), differs from
DGAT2 in that defective fat absorption is not seen in
DGAT1-KO mice. In recent studies, investigators have found
that MGAT2 (29, 31) and MGAT3 (30) possess DGAT activity
(26, 170). Some TAG synthesis also occurs through the dephosphorylation of phosphatidic acid and acylation of the
resultant DAG. Thus, several enzymes take part in the biosynthesis of TAG in intestinal cells.
Use of TAG in lipoprotein assembly. The existence of
multiple pools of DAG (159, 160) and TAG (51, 55, 60, 104,
175, 183, 195) has been known for some time. Using differentiated human colon carcinoma (Caco-2) cells, Luchoomun
and Hussain (115) showed that nascent TAG is used preferentially for chylomicron assembly. TAG is also synthesized de
novo from fatty acyl chains and glycerol phosphate. When
generated through this pathway, however, TAG is only partly
used to assemble nascent apolipoprotein (apo)B-containing
lipoproteins. Most of the TAG synthesized through this pathway enters the cytosolic pool to be used to generate a distinct
pool of DAG. (For a review of this topic, see Ref. 202.) DAG
esterification also occurs in the ER lumen (142), where the
resultant TAG binds to the microsomal triglyceride transport
protein (MTP), which participates in the assembly and secretion of neutral lipids in chylomicrons. This process is described
further in a subsequent section in this review. (For additional
information, also see Refs. 18 and 119.)
Phospholipids
The predominant PL in the lumen of the small intestine is
PC, which is found in mixed micelles that also contain cholesterol and bile salts. The digestion of PLs is carried out
primarily by pancreatic phospholipase A2 (pPLA2) and other
lipases secreted by the pancreas in response to food intake.
These lipases interact with PLs at the sn-2 position to yield
FFAs and lysophosphatidylcholine (21, 182). These products
of lipolysis are removed from the water-oil interface when they
are incorporated into the mixed micelles that form spontaneously when they interact with bile salts. Having both hydro-
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Bile and pancreatic juice provide pancreatic lipase, bile salts,
and colipase, which function cooperatively to ensure the efficiency of lipid digestion and absorption. The importance of
bile to the efficiency of these processes is indicated by the
decreased rate of lipid absorption in humans with bile fistulas.
The greatly reduced concentration of bile acid in the duodenum
of such individuals suggests that bile salts, although possibly
not absolutely necessary for digestion, are essential for the
complete absorption of dietary fats (150). Elevated concentrations of bile salts have been shown to inhibit pancreatic lipase
activity in the duodenum (190). Such inhibition is offset,
however, by colipase, which has been shown in vitro to restore
pancreatic lipase activity under such circumstances (112, 128).
The importance of colipase in the digestion of fat was indicated
in a clinical report of steatorrhea in two brothers with a
congenital absence of colipase, which indicated that the steatorrhea decreased with the administration of colipase (76). It
has also been demonstrated in colipase-deficient mice (41),
which, when placed on a high-fat diet, developed steatorrhea
that was so severe that undigested lipids could be seen in their
feces. When these mice were placed on a low-fat diet, their
ability to digest fat returned to normal. These findings suggest
that colipase plays a critical, but not essential, role in the
digestion of dietary lipids by pancreatic lipases.
Review
INTESTINAL LIPID ABSORPTION
philic and hydrophobic components, bile salts are able to
facilitate micelle formation; MAG and PL enhance their ability
to form mixed micelles. pPLA2-KO mice are indistinguishable
from wild-type controls when fed regular chow, except for
their resistance to diet-induced obesity (84). Increased excretion of TAG, on a high-fat diet, in the feces of pPLA2-KO mice
indicates that pPLA2 deficiency has a greater effect on the
digestion of TAG than that of PL hydrolysis (84). It does not
affect PL hydrolysis and absorption, possibly because its activity is compensated for by other PLA2 enzymes (158).
Cholesterol
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uptake transporter (4) and the ATP-binding cassette (ABC)
proteins ABCG5 and ABCG8 as cholesterol efflux transporters
(14, 106, 113). These three molecules appear to be key players
in the control of the cholesterol absorption from the intestinal
lumen.
ABCG5 and ABCG8, which function as a heterodimer (62),
are critical for the control of sterol absorption. Mutations in the
genes encoding human ABCG5 and ABCG8 transporters cause
␤-sitosterolemia (14, 106, 113), which is characterized by the
accumulation of plant sterols in blood and other tissues as a
result of their enhanced absorption from the intestines and
decreased removal in bile. These proteins are localized at the
canalicular membrane of hepatocytes and at the brush border of
enterocytes. Abcg5/g8 deficiency in mice results in reduced
biliary cholesterol secretion (199) and enhanced phytosterol
absorption (102, 146, 199) but has only minimal effects on the
efficiency of cholesterol absorption (146, 199). The pharmacological induction or overexpression of Abcg5 and Abcg8 in
mice (199 –201) results in a reduction in fractional cholesterol
absorption (i.e., the percentage of cholesterol absorbed from
the intestine, which is determined using a dual-isotope feeding
technique) and indicates that ABCG5 and ABCG8 play a role
in the control of cholesterol absorption under certain
conditions.
The identification of NPC1L1 as a putative cholesterol
transporter in the enterocytes (4) was facilitated by the discovery of the cholesterol absorption inhibitor ezetimibe (4, 59),
which reduces diet-induced hypercholesterolemia (49, 56, 103,
187, 203). NPC1L1 is a glycosylated protein localized at the
brush-border membrane of the enterocyte (95). The deletion of
Npc1l1 in mice results in a reduction in fractional cholesterol
absorption (4). Ezetimibe has been shown to bind to NPC1L1expressing cells and to the intestinal brush border (59). Deletion of Npc1l1 also results in the elimination of the binding
capacity of the brush border (59), which indicates that NPC1L1
is a target of ezetimibe.
A sterol regulatory element in the promoter and a sterolsensing domain of NPC1L1 appear to regulate cholesterol
absorption in response to cholesterol intake. Expression of
Npc1l1 is enhanced in the cholesterol-depleted porcine intestine and suppressed in mice placed on a cholesterol-rich diet
(83). Most of the NPC1L1 in the body is found in intracellular
membranes. However, cholesterol deprivation induces its
translocation to the plasma membrane, where it can pick up
cholesterol and transport it to the ER for esterification and
packaging into nascent lipoproteins (50, 198).
Reducing the expression of NPC1L1 at the level of transcription may reduce cholesterol absorption. Activation of the
nuclear receptor peroxisome proliferator-activated receptor
(PPAR)␦/␤ by the synthetic agonist GW610742 has been
shown to reduce cholesterol absorption by decreasing Npc1l1
expression without altering the expression of Abcg5 and Abcg8
(185). A decrease in Npc1l1 expression has also been observed
following treatment of human colon-derived Caco-2 cells with
ligands for PPAR␦/␤ but not for PPAR␥ or PPAR␣ (185).
Absorption: other regulatory factors. The nuclear liver X
receptors (LXRs) LXR␣ (expressed mainly in the liver, kidney,
intestine, spleen, and adrenals) and LXR␤ (expressed ubiquitously) regulate pathways involved in the metabolism of cholesterol and in lipid biosynthesis. LXR target genes have been
shown to be involved in cholesterol and lipid homeostasis. (For
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Cholesterol in the body represents both endogenous
sources (produced in the liver and peripheral tissues) and
dietary sources absorbed from the intestine (186). The
human diet provides ⬃400 mg of cholesterol daily, and the
liver secretes ⬃1 g daily (66, 194). Approximately 50% of
the cholesterol in the intestine is absorbed; the remainder is
excreted in feces (10, 39).
Digestion. Only nonesterified cholesterol can be incorporated into bile acid micelles and absorbed by enterocytes. Most
dietary cholesterol exists in the form of the free sterol, with
only 10 –15% existing as the cholesteryl ester. The latter must
be hydrolyzed by cholesterol esterase to release free cholesterol for absorption. Cholesterol is only minimally soluble in
an aqueous environment (82, 177) and thus must be partitioned
into bile salt micelles prior to absorption. It usually enters these
micelles along with TAGs and PLs, ionized and nonionized
FAs, MAGs, and lysophospholipids to form mixed micelles
(74, 196). These micelles are transported to the brush border of
the enterocyte, where cholesterol is absorbed. Its absorption
depends on the presence of bile acids in the intestinal lumen
(191) and correlates directly with the total bile acid pool (149).
Absorption: cholesterol uptake. Cholesterol must pass
through a diffusion barrier at the intestinal lumen-enterocyte
membrane interface before it can interact with transporter
proteins responsible for its uptake and subsequent transport
across the cellular brush border. Bile salt micelles facilitate the
transfer of cholesterol across the unstirred water layer. The
mechanism by which the cholesterol in micelles is taken up by
the cell and crosses the brush-border membrane is still under
investigation. Cholesterol absorption had long been considered
an energy-independent, simple, passive diffusion process.
However, it is taken up by the enterocyte with relatively high
efficiency compared with structurally similar phytosterols
(130). New evidence strongly suggests that a transporterfacilitated mechanism is involved. Interindividual differences
and interstrain variations in the efficiency of intestinal cholesterol absorption (195, 196) support this suggestion, as does the
discovery that multiple genes (4, 14, 106, 113) participate in
the regulation of cholesterol absorption and several molecules
appear to inhibit it (59).
Absorption: cholesterol transport. Several proteins have
been investigated for their potential roles as intestinal cholesterol transporters, but evidence for their direct role in the
uptake of cholesterol remains elusive. Studies in genetically
modified animal models have helped investigators gain important insights into the mechanisms of transport and identity of
transporter proteins. Through these studies, investigators have
identified Niemann-Pick C1 like 1 (NPC1L1) as a cholesterol
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INTESTINAL LIPID ABSORPTION
AJP-Endocrinol Metab • VOL
important for bulk entry of cholesterol into nascent chylomicrons. Reesterification of the absorbed cholesterol within the
enterocyte enhances the diffusion gradient to favor the entry of
intraluminal cholesterol into the cell and is therefore an important regulator of cholesterol absorption from the intestine.
Thus, inhibition of ACAT by pharmacological intervention
(38, 73) or deletion of Acat2 (26) significantly reduces the rate
of cholesterol absorption.
It has also been suggested that ATP-binding cassette transporter A1 (ABCA1) plays a role in the control of cholesterol
absorption. ABCA1 was initially thought to be localized to the
apical membrane (157); more recent studies have provided
evidence suggesting that it is present in the basolateral membrane of chicken enterocytes (132) and human Caco-2 cells
(138). Our studies in Caco-2 cells and in the apoA1-KO mouse
model showed for the first time that basolateral efflux (secretion) of cholesterol occurs in high-density apoB-free/apoA-Icontaining lipoproteins (Fig. 1) (91, 93). The importance of
ABCA1 in the biogenesis of HDL in the intestine was demonstrated by deleting intestinal Abca1, which resulted in a 30%
decrease in plasma HDL cholesterol levels (24). Enterocytes
deficient in ABCA1 absorb smaller amounts of cholesterol
(24). Thus, HDL contributes considerably to cholesterol absorption from the intestine. The origin of HDL particles in
mesenteric lymph fluid has been a subject of considerable
controversy (11, 53, 117, 139, 152, 169, 188). The measurement of cholesterol in lymph led to the hypothesis that HDL is
not important in cholesterol transport. However, Brunham
et al. (24) recently demonstrated that the HDL in lymph is
dependent on the activity of hepatic ABCA1 and enters the
lymph from plasma. Thus, quantification of HDL in lymph
may not provide an accurate assessment of the extent of
cholesterol absorption via this pathway.
Vitamin E
Vitamin E is one of the most abundant lipid-soluble antioxidants found in the plasma and somatic cells of higher
mammals. Vitamin E exists in two forms, as tocopherols and
tocotrienols, that vary dramatically in terms of biological
activity due to variations in bioavailability and in intrinsic
antioxidant properties. The hydrophobic nature of vitamin E
creates a major challenge to living organisms in maintaining
adequate uptake, transport, and delivery of this vitamin to
various tissues.
Vitamin E absorption. Micelle formation is required for the
absorption of vitamin E (57, 171). Pancreatic enzymes may
also aid in its absorption (121); this is suggested by the finding
of vitamin E deficiency in patients with cystic fibrosis, who do
not secrete pancreatic enzymes (12, 48, 70, 172, 193).
The mechanism of absorption of vitamin E from the intestine
is similar to the mechanism involved in the transport of other
lipid molecules in vivo and involves molecular, biochemical,
and cellular mechanisms closely related to overall lipid and
lipoprotein homeostasis (22, 67, 75, 100, 101, 179 –181). The
uptake of vitamin E from the intestine has traditionally been
assumed to be a simple process of passive diffusion. However,
in a study in Caco-2 cells, it was shown to be a rapid, saturable,
temperature-dependent process (7). Recent studies suggest that
SR-BI plays a role in vitamin E absorption (154). Vitamin E
absorption from the intestine is thought to occur predominantly
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a list of target genes and their regulation, see Ref. 174.) After
activation by natural ligands (e.g., oxysterols), the LXR forms
a heterodimer with the retinoid X receptor (96, 97) and binds
to specific LXR response elements in the promoter regions of
their target genes to activate gene transcription. LXR target
genes include those that express proteins involved in the efflux
of cholesterol from the cell (155, 157, 174, 189) as well as bile
acid synthesis (174) and lipogenesis (174). Thus, global LXR
activation by synthetic agonists has a plethora of effects,
including elevated high-density lipoprotein (HDL) levels (25,
28, 98, 126, 147, 163, 178), hypertriglyceridemia (156, 163),
hepatic steatosis (65), increased excretion of cholesterol in bile
(147, 201), reduced efficiency of cholesterol absorption from
the intestine (103, 157, 159, 191, 206), and increased loss of
neutral sterols in feces (201).
Other transporters, such as scavenger receptor class B type I
(SR-BI), which is localized both at the apical and basolateral
membranes of enterocytes (27), have also been suspected of
having a role in the control of cholesterol absorption. The
possibility that SR-BI is a cholesterol transporter is suggested
by the observation that intestine-specific overexpression of
SR-BI in mice leads to an increase in cholesterol and TAG
absorption in short-term absorption experiments (17). The
importance of the FA translocase CD36 (which is also expressed in epithelial cells lining the small intestine) in FA
absorption is well established. CD36 has also been implicated
as the cholesterol transporter in brush-border membranes. Additionally, overexpression of CD36 in COS-7 cells has been
shown to enhance cholesterol uptake from micellar substrates
(184). In another study, CD36-null mice showed a significant
reduction in cholesterol transport from the intestinal lumen to
the lymphatic system (133). Decreased cholesterol uptake has
been shown in brush-border membrane vesicles prepared from
the proximal (but not distal) intestine of SR-BI-KO mice (184)
and in brush-border membrane vesicles and Caco-2 cells preincubated with antibodies to SR-BI (71). However, targeted
disruption of SR-BI in mice has little effect on in vivo intestinal
cholesterol absorption (3, 120, 192), which suggests that SR-BI
might not be essential for absorption of cholesterol from the
intestine.
Another potential step in the regulation of cholesterol absorption involves two ER membrane-localized enzymes, acylCoA:cholesterol acyltransferase 1 (ACAT1) and ACAT2, that
catalyze the esterification of intracellular cholesterol (107).
ACAT1 is expressed in many tissues (36, 61), but its level of
expression in the mouse small intestine is very low (125). By
contrast, ACAT2 expression is restricted to the small intestine
and liver (6, 35, 137). ACAT2 is highly specific for cholesterol
and does not esterify plant sterols. It is the predominant
enzyme responsible for the synthesis of cholesterol esters and
their subsequent secretion with lipoproteins. ACAT2 deficiency results in a considerable decrease in the rate of cholesterol absorption (26). The rate of cholesterol esterification in
the presence of these enzymes is notably enhanced by substrate
availability, but, as we demonstrated recently, it is inhibited by
product accumulation. This inhibition is relieved by MTP (94),
which transfers cholesterol esters from the ER membranes to
nascent apoB-lipoproteins. The importance of MTP in cholesterol absorption has been well documented (85, 86, 89).
Approximately 70 – 80% of cholesterol entering the lymphatic system is esterified, which suggests that esterification is
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INTESTINAL LIPID ABSORPTION
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through the secretion of chylomicrons into the lymphatic system. Consistent with this hypothesis is the observation that
vitamin E absorption is dependent on the availability of oleic
acid for triglyceride synthesis and chylomicron assembly and is
inhibited by MTP inhibitors (7). The importance of alternative
pathways for vitamin E absorption has also been suggested by
the observation that symptoms of vitamin E deficiency are
ameliorated after treatment with high doses of vitamin E in
patients deficient in chylomicrons. Indeed, intestinal vitamin E
absorption may also occur via direct secretion from epithelial
cells into the portal venous circulation by HDL efflux. This
HDL-dependent mechanism was recently characterized in
Caco-2 cells (7). Whether intestinal ABCA1 or other ABC
transporters are also critical for the absorption of vitamin E
from the intestine and for steady-state plasma ␣-tocopherol
levels remains to be seen.
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Vitamin A. The de novo synthesis of compounds with
vitamin A activity is limited to plants and microorganisms.
Higher animals must obtain vitamin A from the diet. The main
dietary forms of preformed vitamin A are carotenoids in fruits
and vegetables and long-chain FA esters of retinol in foods of
animal origin (145). Carotenoids are either cleaved to generate
retinol or absorbed intact, whereas retinyl esters must be
completely hydrolyzed within the intestinal lumen to release
free retinol before retinol can be taken up by enterocytes.
Hydrolysis of the retinyl esters requires lipase activity. The
products of TAG hydrolysis provide a better milieu for the
solubilization of vitamin E in mixed micelles.
Free retinol is taken up by intestinal mucosal cells (44). In
studies conducted in Caco-2 cells (151) and intestinal segments, investigators have found that saturable carrier-mediated
processes at physiological concentrations (81) and nonsat-
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Fig. 1. Intestinal lipid absorption. Products of lipid hydrolysis are solubilized in micelles and presented to the apical membranes of enterocytes. This membrane
harbors several transport proteins that participate in the uptake of various types of lipids. Niemann-Pick C1 like 1 (NPC1L1) is a protein involved in cholesterol
uptake. CD36 and fatty acid (FA) transport protein (FATP) have been shown to participate in FA transport, whereas scavenger receptor class B type I (SR-BI)
is involved in vitamin E (Vit E) uptake. In the cytosol, FA-binding protein (FABP) and cellular retinol-binding protein (CRBP) transport FAs and retinol (R),
respectively. Acyl-CoA:cholesterol acyltransferase (ACAT), diacylglycerol acyltransferase (DGAT), and lecithin:retinol acyltransferase (LRAT) are found in the
endoplasmic reticulum (ER) membrane, where they facilitate the esterification of cholesterol, monoacylglycerols (MAG), and retinol, respectively. These
esterified products are incorporated into apolipoprotein (apo)B48-containing chylomicrons (CM) in a microsomal triglyceride (TG) transport protein
(MTP)-dependent manner. The newly synthesized prechylomicrons are transported in specialized vesicles to the Golgi apparatus for further processing and for
secretion. In addition, enterocytes express ATP-binding cassette (ABC) transporter A1 on the basolateral membrane to facilitate the efflux of cholesterol. C, free
cholesterol; RE, retinyl ester; CE, cholesteryl ester; AIV, apolipoprotein A-IV.
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INTESTINAL LIPID ABSORPTION
ASSEMBLY, SECRETION, AND REGULATION
OF INTESTINAL LIPOPROTEINS
The major lipoproteins secreted by the intestine are VLDL
and chylomicrons. Of these, the chylomicrons are synthesized
AJP-Endocrinol Metab • VOL
exclusively in the intestine to transport dietary fat and fatsoluble vitamins into the blood (Fig. 1). Chylomicrons are
primarily very large, spherical TAG-rich particles (5, 58) that
also contain PLs, cholesterol, vitamin E, vitamin A, and protein. The lipoprotein core contains TAG, cholesteryl esters, and
fat-soluble vitamins, whereas the surface contains a monolayer
of PLs (mainly phosphatidylcholine), free cholesterol, and
protein (127, 204, 205). A key structural component of the
chylomicron is the huge, hydrophobic, nonexchangeable protein apoB48. Other proteins associated with nascent chylomicrons (which are synthesized in enterocytes) are apoA-I, apoAIV, and apoCs. apoB48 synthesis is generally believed to be
constitutive (88). However, the amount of lipids transported
during the postprandial state is severalfold greater than that
transported during the fasting state. Increased transport of fat
with similar amounts of apoB48 occurs because of an increase
in the size of the particles during the postprandial state (42, 43,
54, 63, 72, 173). Fat feeding also increases the expression of
apoA-IV, which serves as a surface component for apoB48
particles in the enterocyte (77, 135).
It has been proposed that chylomicron assembly involves the
synthesis of “primordial lipoproteins” followed by their core
expansion, which results in the formation of “nascent lipoproteins” (88). This basic proposal was later expanded to suggest
that chylomicron assembly may involve three independent
steps: assembly of primordial lipoproteins, formation of lipid
droplets, and core expansion (85). Subsequently, different
biochemical signposts for various biosynthetic milestones were
articulated (89). The association of a preformed PL with
nascent apoB was proposed to determine the assembly of
primordial lipoproteins. An increase in the amount of nascent
TAG would serve as an indicator of the synthesis of larger
lipoproteins, and retinyl esters were proposed as markers of the
completion of chylomicron assembly.
Chylomicron assembly occurs mainly in the ER. These
particles are then transported to the cis-Golgi in prechylomicron transport vesicles (PCTVs) (18, 105, 119). Budding of the
PCTVs has been shown to require liver FABP (135). Prechylomicrons are very large and carry a unique cargo compared
with vesicles that carry nascent proteins (205). Siddiqi et al.
(165) showed that chylomicrons are exported from the ER in
large vesicles (250 nm) by a coat protein complex II (COPII)independent mechanism, although COPII proteins are found on
PCTVs. These investigators demonstrated further that COPIIinteracting proteins (Sar1, Sec23/24, and Sec13/31) are needed
to form lipid vesicles that can fuse with the Golgi complex.
The unique presence of vesicle-associated membrane protein 7
in the intestinal ER and on PCTVs has been suggested to play
a role in the export of chylomicrons from the ER to the
cis-Golgi (166). Recently, it was shown that an isoform of
protein kinase C (PKC), PKC␨, is required for PCTV budding
(167). Thus, chylomicrons are transported on unique particles,
different from those used for protein transport, by intestinal
cells. Similarly, unique particles have been shown to transport
hepatic lipoproteins in the liver (164).
Various mechanisms have been shown to regulate the secretion of lipoproteins from the intestine. Intestinal lipoprotein
production is affected by the transcription of apoB, which has
generally been believed to be constitutive. Previously, it was
known that apoB levels change primarily through co- and
posttranslational mechanisms; however, Singh et al. (168)
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urable diffusion-dependent processes at pharmacological concentrations (80) of free retinol are involved in retinol uptake.
After cellular uptake, the intercellular retinol-binding proteins
(CRBPs) CRBP-I and CRBP-II immediately sequester free
retinol. CRBP-I is expressed in many tissues, whereas CRBP-II
is expressed primarily in the absorptive cells of the small
intestine. CRBP-II is one of the most abundant soluble proteins
in the jejunal mucosa, which indicates that it may be uniquely
suited for the absorption of retinol from the intestine (109, 136,
140, 141). In studies conducted in retinoid-deficient rats (153)
and in rats placed on diets containing long-chain FAs (176),
investigators found that CRBP-II mRNA expression increased
in the small intestine. In studies carried out in Caco-2 cells,
investigators found that overexpression of CRBP-II or treatment with retinoic acid (which is associated with increased
CRBP-II mRNA expression) resulted in increased absorption
and intracellular esterification of retinol. In CRBP-II-KO mice,
investigators found that CRBP-II plays an important (albeit not
essential) role in the absorption of vitamin A from the intestine
(47). Some of the free retinol in the enterocytes remains
associated with CRBP, but much of the retinol is usually
esterified by lecithin:retinol acyltransferases (LRATs) and
stored within the cell (116). The recent characterization of the
LRAT-KO mouse [in which no detectable tissue retinyl esters
were found (9)] has largely resolved the question of whether
enzymes such as ARAT are physiologically involved in retinol
esterification in the intestine.
Metabolic studies have revealed that most of the retinyl
esters in plasma are present in small chylomicrons; significant
amounts are found in large chylomicrons, and smaller amounts
are found in very-low-density lipoproteins (VLDL) (108).
Studies have been carried out in differentiated Caco-2 cells
under postprandial conditions to determine the mechanism of
retinol secretion by the intestine. In these studies, investigators
found that a significant amount of retinyl ester was secreted
mainly with chylomicrons independent of the rate of retinol
uptake and intracellular levels of free or esterified retinol (134).
Pluronic L81, which inhibits the secretion of chylomicrons,
decreased the secretion of retinyl ester and did not result in
their increased secretion with smaller lipoproteins. This suggests that intestinal retinyl ester secretion is a highly specific
and regulated process that is dependent on the assembly and
secretion of chylomicrons. A significant amount of retinol is
also secreted into the portal circulation, probably as free
retinol; this is expected to be physiologically significant in
pathological conditions that affect the secretion of chylomicrons (79). However, very little is known about the regulation
of the retinol secretion by this pathway. Under fasting conditions, Caco-2 cells secrete mainly free retinol unassociated
with lipoproteins (134). The secretion of free retinol may
require facilitated transport. This notion is supported by the
marked inhibition of the free retinol efflux into the basolateral
medium by glyburide, a known inhibitor of the ABCA1 transporter (46). Mechanisms regulating retinol output through
these pathways are not well understood.
Review
INTESTINAL LIPID ABSORPTION
AJP-Endocrinol Metab • VOL
tion of IRE1␤ may be useful for avoiding a diet-induced hyperlipidemia.
Intestinal lipid absorption has been shown to exhibit diurnal
variations in rodents and humans (8, 23, 118, 129, 143).
Although plasma lipid concentrations are maintained within a
narrow physiological range, several factors (e.g., plasma clearance, cholesterol biosynthesis, and hormonal changes) can lead
to changes in plasma lipids. It was recently demonstrated that
diurnal variations in plasma lipid levels in rodents are due to
changes in MTP levels (143). Lipid absorption was higher at
2400 than at 1200 because of the rodents’ nocturnal feeding
behavior. Using in situ loops and isolated enterocytes, it was
demonstrated that circadian variations were due to changes in
intestinal activities and not because of variations in gastric
functions. Further studies have revealed that intestinal expression of MTP also has diurnal variations. Consistent with this
finding, the transcription rate for microsomal triglyceride transfer protein (mttp) was high at 2400 compared with 1200. Thus,
it appears that MTP expression and lipid absorption are maximized to absorb more lipids at mealtime. The diurnal variations in MTP, in turn, may be responsible for the change in
total plasma lipids and apoB lipoproteins (143).
CONCLUSIONS
The absorption of lipids from the intestinal lumen into the
enterocytes and their subsequent secretion into circulation is a
complex process. Membrane transporters regulate lipid uptake
on the apical surface of the brush border of the enterocyte. An
essential role for NPC1L1 in cholesterol absorption and for the
coordinated activities of ABCG5 and ABCG8 in limiting
excess cholesterol uptake is well established. Several proteins
involved in FA uptake have also been identified. Transport of
lipids from the plasma membrane to the ER involves the
activity of intracellular trafficking proteins. Lipids that have
been absorbed into the ER are resynthesized and packaged into
chylomicrons; this process is dependent on apoB and MTP
activity. Specialized vesicles carry these chylomicrons to the
basolateral membrane of the cell for secretion. Posttranscriptional degradation of MTP by IRE1␤ provides a way to
modulate intestine-specific regulation of lipoprotein assembly
and absorption and may be useful for avoiding diet-induced
hyperlipidemias. Recent findings concerning the basolateral
efflux of cholesterol as high-density apoA-I-containing lipoproteins will help us identify additional targets for the
development of drugs that may suppress cholesterol absorption
to reduce hypercholesterolemia and the risk for cardiovascular
disease.
GRANTS
This work was supported in part by National Institute of Diabetes and
Digestive and Kidney Diseases Grant DK-46700 and a Grant-in-Aid from the
American Heart Association to M. M. Hussain.
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