Departments of Internal Medicine, Molecular Biology, and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110
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ABSTRACT |
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Efficient uptake and channeling of long-chain fatty acids (LCFAs) are critical cellular functions. Although spontaneous flip-flop of nonionized LCFAs from one leaflet of a bilayer to the other is rapid, evidence is emerging that proteins are important mediators and/or regulators of trafficking of LCFAs into and within cells. Genetic screens have led to the identification of proteins that are required for fatty acid import and utilization in prokaryotic organisms. In addition, functional screens have elucidated proteins that facilitate fatty acid import into mammalian cells. Although the mechanisms by which these proteins mediate LCFA import are not well understood, studies in both prokaryotic and eukaryotic organisms provide compelling evidence that uptake of LCFAs across cellular membranes is coupled to esterification by acyl-CoA synthetases. This review will summarize results of studies of non-protein-mediated and protein-mediated LCFA transport and discuss how these different mechanisms may contribute to cellular metabolism.
long-chain fatty acid transport; permeation
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FATTY ACIDS ARE CRITICAL MOLECULES FOR DIVERSE CELLULAR FUNCTIONS |
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Long-chain fatty acids (LCFAs) are fuels that can
be used to generate ATP efficiently primarily through -oxidation in
mitochondria and peroxisomes. The capacity of vertebrate organisms to
store this fuel as triglycerides in cytosolic lipid droplets is an
important adaptation for survival during periods of nutritional
deprivation. In addition, fatty acids are precursors for the
biosynthesis of complex membrane lipids. The acyl chain composition of
these lipids helps to determine overall membrane structure and
function. Fatty acids are also precursors for lipid-signaling molecules
and serve as ligands for transcription factors that control cellular
metabolic gene expression.
LCFAs can be generated endogenously in cells from de novo
biosynthesis, hydrolysis of triglycerides, and recycling of membrane lipids, or they can be imported into cells from exogenous sources. De
novo LCFA biosynthesis in prokaryotic and eukaryotic cells is catalyzed
by the highly regulated enzymes acyl-CoA carboxylase and fatty acid
synthase (FAS). Prokaryotic organisms require exogenous fatty acids
under hypoxic conditions and under circumstances in which the activity
of FAS is inhibited and fatty acids are supplied as the sole carbon
source in the media. Although most eukaryotic cells are capable of de
novo fatty acid synthesis, cells with large requirements for fatty acid
-oxidation, such as cardiac myocytes, rely on import of exogenous
LCFAs to provide this critical metabolic fuel. Cells that store
potential energy in the form of triglyceride, such as adipocytes, have
efficient mechanisms for both LCFA import and export.
How cells import LCFAs has been the subject of much investigation. Experimental evidence provides support for two classes of transport mechanisms, non-protein-mediated and protein-mediated permeation. Much of the literature has focused on determination of which single mechanism best describes LCFA transport; however, there is evidence to suggest that both types of transport play important roles, albeit under different physiological or pathophysiological conditions.
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FATTY ACIDS CAN FLIP-FLOP RAPIDLY ACROSS MODEL MEMBRANES |
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Amphiphilic LCFAs are poorly soluble in aqueous solutions. Although these molecules are ionized at physiological pH, they readily partition into membranes in which they may be protonated [the ionization constant (pKa) in the environment of the phospholipid bilayer is 7.6, whereas the pKa is 4.5 in an aqueous compartment where the pH is 7.4 (27)]. Movement of LCFA anions from one leaflet to the other is slow (25, 55); however, movement of nonionized LCFAs from one leaflet to the other (flip-flop) is extremely rapid. Thus it has been proposed that LCFAs enter cells by a process involving adsorption to the membrane, protonation, flip-flop within the membrane, and desorption into the cytosolic space (29). This model does not require facilitation by membrane proteins.
Initial evidence for this non-protein-mediated mechanism of LCFA
transport came from in vitro studies showing rapid rates of flip-flop
of nonionized LCFAs in unilammelar phosphatidylcholine (PC) membrane
vesicles. Flip-flop can be monitored by measuring the quenching of a
pH-sensitive fluorescent probe, pyranin, that is trapped on the inside
of the vesicles. When free LCFAs are added to the aqueous compartment,
they rapidly adsorb to the membranes (not rate limiting), and changes
in fluorescence represent ionization of the LCFA after its appearance
at the inner leaflet. In large unilammelar vesicles (LUVs, diameter 100 nm), addition of high concentrations of free LCFAs leads to flip-flop
within milliseconds, with a pseudomolecular rate constant for flip-flop
(KFAH) of 15 s1 and a half-time
(t1/2) of 23 ms (35). Studies of
flip-flop in model membranes have been extended by use of intracellular pH indicators to measure intracellular acidification upon flip-flop of
fatty acids across the plasma membrane of pancreatic
-cells (28) and adipocytes (13). In
-cells, the
rate of acidification upon addition of extracellular LCFA is slower
than for LUVs by several orders of magnitude, with a
t1/2 of 60 s. Both in LUVs and in cells,
the lack of dependence of the rate of acidification on fatty acid chain
length or structure (fatty acid dimers or alkylamines have similarly
rapid rates) suggests a non-protein-mediated mechanism.
Monitoring intravesicular or intracellular pH changes provides a means for real-time measurements of LCFA flip-flop. Nonetheless, several caveats to these interpretations should be noted. Most of these studies have been performed using supraphysiological free LCFA concentrations that may contribute to the high rates observed. The volume in LUVs (diameter 100 nm) is less than that of a cell (average diameter 20 µm) by a factor of 104; thus rates of flip-flop measured by changes in concentration (pH) rather than the number of molecules will be higher in smaller volume compartments. Synthetic PC vesicles may not reproduce with fidelity the behavior of cellular membranes that contain a mixture of complex lipids and proteins (38). Although intracellular acidification is consistent with increases in intracellular LCFAs, and intracellular alkalinization is consistent with decreases in intracellular LCFAs (13), these measurements are indirect measures of the movement of the LCFAs themselves. Finally, flip-flop of nonionized LCFAs within the membrane and subsequent ionization are not necessarily the equivalent of transport of LCFAs from the extracellular aqueous space to the intracellular aqueous space for metabolic utilization. Desorption of LCFAs (particularly those of longer chain lengths and higher degrees of saturation) from phospholipid bilayers may become rate limiting (75).
Some of these caveats have been addressed in studies using the soluble
fluorescent free LCFA indicator ADIFAB to measure the appearance of
LCFAs in the aqueous phase of the interior of vesicles (38) and red blood cell ghosts (37). In these
studies, LCFAs were added to LUVs (diameter 100 nm) or giant
unilammelar vesicles (GUVs, diameter 200 nm) or to red blood cell
ghosts by use of LCFA-BSA complexes with unbound (free) LCFA
concentrations in the 14- to 190-nm range. By measuring the changes in
fluorescence of ADIFAB trapped within ghosts, the investigators
measured the appearance of LCFAs in the internal aqueous environment.
As predicted, increase in the diameter of PC/cholesterol vesicles from
100 nm (LUVs) to 200 nm (GUVs) decreases the rate of flip-flop by an order of magnitude (38). Nonetheless, rapid rates of
flip-flop are observed in red blood cell ghosts, with a constant for
flip-flop (Kff) ranging from 0.31
to 3.0 s
1 and without evidence of saturation or protease
sensitivity (37). This study shows that LCFA permeation
across naturally occurring cellular membranes can be extremely rapid
and may not occur through protein-mediated mechanisms. This study does
not rule out the possibility that alternate or additional mechanisms
may be used for LCFA transport for cells with high LCFA metabolic
requirements (38), particularly in settings of low
physiological unbound LCFA concentrations (low nanomolar range).
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GENETIC SCREENS IDENTIFY PROTEINS REQUIRED FOR FATTY ACID UPTAKE IN ESCHERICHIA COLI |
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The first proteins involved in LCFA transport were identified by genetic studies in the gram-negative bacteria E. coli. These simple organisms transport LCFAs across an outer membrane consisting of lipopolysaccharide and phospholipid, a layer of peptidoglycan associated with the inner leaflet of the outer membrane, the periplasmic space, and a cytoplasmic or inner membrane. This envelope is normally impermeable to LCFAs. Transport across this barrier is necessary under growth conditions in which de novo LCFA biosynthesis is inhibited by cerulenin and LCFAs are provided as the sole carbon source. Screens of mutant cells grown under such conditions led to identification of two genes required for LCFA transport in E. coli (reviewed in Ref. 8). The fadL gene encodes an outer membrane-bound fatty acid transport protein (FATP) that contains separable regions involved in fatty acid binding and transport (40, 50). The fadD gene product is an inner membrane-associated acyl-CoA synthetase (ACS) (9, 36). The observation that LCFA transport for utilization in metabolic pathways is intimately linked to esterification led Klein et al. (36) to propose a mechanism termed "vectorial acylation." Esterification of imported LCFAs at the inner aspect of the membrane concomitant with transport would effectively deplete intracellular concentrations of free LCFAs and render the permeation step irreversible. The action of ACS may be the limiting step in LCFA permeation, although ACS may function together with other membrane proteins to transport LCFAs across the membrane.
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KINETIC EVIDENCE FOR PROTEIN-MEDIATED TRANSPORT IN EUKARYOTIC CELLS |
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Kinetic analyses of LCFA transport in mammalian cells by use of
radiolabeled substrates have also suggested a role for proteins in
mediating this cellular function. Initial rates of LCFA transport into
isolated rat adipocytes are maximal and linear for 15 s, are a
function of concentration of unbound LCFA in the medium, and
demonstrate both saturable and nonsaturable components (3, 66,
67). The saturable components are observed primarily at LCFA-to-BSA (LCFA/BSA) ratios <3.0, consistent with the physiological range. In normal human serum, the average LCFA-to-albumin
(LCFA/albumin) ratio is 0.74 (53). The nonsaturable
components of LCFA uptake are observed at LCFA/BSA ratios 3.0.
Although such ratios exceed the physiological range, LCFA/albumin
ratios as high as 7.5 have been reported in pathophysiological states
(39). The rate constant for saturable transmembrane influx
in adipocytes (Ks = 2.9 s
1)
is 10- to 30-fold higher than the rate constant for nonsaturable uptake
(Kns = 0.26-0.10 s
1,
with t1/2 = 2.7-6.6 s, depending on
LCFA-BSA binding constants used to calculate free fatty acid
concentrations) (66). The saturable component is specific
for LCFAs but not for medium-chain fatty acids, and competition for
transport among a variety of LCFAs and LCFA analogs has been
demonstrated (2). Studies in which saturable LCFA uptake
is inhibited by prior protease treatment of the cell surface suggest
that, in higher organisms, LCFAs are transported by a protein-mediated
mechanism (2, 3, 45, 61). Such a mechanism would
potentially provide a means for efficient LCFA import, when fatty acid
concentrations are in the physiological low nanomolar range, and a
means for regulation of LCFA permeation.
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PROTEINS THAT BIND FATTY ACIDS AT THE CELL SURFACE FACILITATE LCFA TRANSPORT |
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To identify specific proteins that facilitate LCFA transport in mammalian cells, initial efforts took advantage of the observation that many transport proteins bind their substrates specifically with high affinity. A plasma membrane fatty acid binding protein (FABPpm) was purified by oleate-agarose affinity chromatography from hepatocytes, adipocytes, jejunal enterocytes, and cardiac myocytes and was proposed to play a role in fatty acid import (51, 60, 62). This protein shares amino acid identity with mitochondrial aspartate aminotransferase (mAspAT) (68), a protein synthesized on free polysomes in the cytosol, with an amino-terminal mitochondrial targeting sequence that is clipped after mitochondrial translocation. Expression of the cDNA encoding mAspAT in fibroblasts increases saturable LCFA uptake (34). Antibodies directed against FABPpm bind the plasma membrane of cells and diminish fatty acid import (63, 76). These studies are consistent with a model in which FABPpm is targeted to the cell surface, where it facilitates LCFA transport; although the mechanism by which this globular protein is targeted to and tethered at the plasma membrane after synthesis on free polysomes in the cytoplasm remains unclear.
CD36 (also known as fatty acid translocase or FAT) was identified to play a role in fatty acid import on the basis of its ability to bind a sulfosuccinimidyl LCFA derivative that inhibits LCFA import (30). This 88-kDa plasma membrane was cross-linked to radiolabeled sulfosuccinimidyl-oleate, purified, and subsequently cloned (1). When overexpressed in cultured fibroblasts, CD36 increases saturable, high-affinity, phloretin-sensitive LCFA uptake and utilization (33). Mice with CD36 overexpression in muscle under the control of the muscle creatine kinase gene promoter have leaner body mass, enhanced ability to oxidize fatty acids in response to stimulation/contraction, and decreased blood levels of triglycerides and fatty acids. (32), Moreover, CD36 knockout mice have increased serum fasting levels of nonesterified free fatty acids and triglycerides and reduced uptake of [3H]oleate in isolated adipocytes, which is most prominent at low oleate-to-BSA ratios, consistent with impairment of the high-affinity component of the LCFA transport system (19). Uptake of LCFA analogs is reduced in heart (50-80%), skeletal muscle (40-70%), and adipose tissue (60-70%) in CD36-null mice (14). Residual fatty acid uptake in these tissues and preserved fatty acid uptake into other tissues such as liver, kidney, lung, and small intestine suggest that, although CD36 activity accounts for a significant fraction of LCFA uptake activity, other transport mechanisms exist.
CD36 was previously identified as a platelet integral membrane glycoprotein that functions as a multiligand scavenger receptor. In addition to binding reversibly to LCFAs (5), CD36 binds thrombospondin-1, modified low-density lipoprotein, retinal photoreceptor outer segments, Plasmodium falciparum malaria-parasitized erythrocytes, sickle erythrocytes, anionic phospholipids, apoptotic cells, and collagens I and IV (20). CD36 has two transmembrane domains with a large glycosylated extracellular loop. Although CD36 is a plasma membrane protein, recent evidence suggests that distribution of CD36 between intracellular membranes and the plasma membrane may play a role in regulation of this protein's function in LCFA uptake. In skeletal muscle giant sarcolemmal vesicles (GSVs), maximal velocity for palmitate uptake is increased by short-term (30-min) electrical stimulation of muscle contraction before harvest of GSVs. The increased palmitate uptake is associated with increased expression of CD36 in GSVs. Moreover, subcellular fractionation of rat skeletal muscles shows redistribution of CD36 from intracellular membranes to the sarcolemma with electrical stimulation, suggesting that localization may play an important role in activity and regulation of CD36-mediated transport (10).
Loss of function of CD36 has been implicated in pathophysiological states. CD36 deficiency has been linked to insulin resistance and abnormal fatty acid metabolism in the spontaneously hypertensive rat (SHR) model (4, 26, 52), although the findings are not consistent between different SHR strains (22). In humans, CD36 deficiency has been reported in individuals with heart muscle hypertrophy or dysfunction (69), a finding that is particularly intriguing given the importance of fatty acid metabolism in normal heart function and its known perturbation in hypertrophy and heart failure. Given the high frequency of CD36 deficiency in the Japanese population studied (74) and the known decreases in fatty acid oxidation in hearts affected by hypertrophy and heart failure (7), it will be important to carry out prospective epidemiological studies to document that the incidence of these common heart diseases is increased in individuals with CD36 deficiency compared with individuals who have normal CD36 expression.
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PROTEINS IDENTIFIED IN A FUNCTIONAL SCREEN FOR LCFA UPTAKE |
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An expression cloning approach identified two adipocyte proteins that facilitate the import of LCFAs when expressed in mammalian cells (54). The first of these proteins, fatty acid transport protein 1 (FATP1), is a 646-amino acid integral plasma membrane protein expressed in cells and tissues with high-level fatty acid import for metabolism or storage. Expression of FATP1 in mammalian cells increases import of LCFAs and very long-chain fatty acids (VLCFAs), but not medium-chain substrates. FATP1 has a distinct membrane topology (42) with a long hydrophobic amino-terminal region of 190 amino acids containing three stretches of sequence independently capable of directing integral membrane association of reporter sequences. The extreme amino terminus of FATP1 faces the extracellular/lumenal space, residues 1-190 contain at least one transmembrane domain, and the carboxyl terminus of FATP1 faces the cytosolic space. Residues 191-257 are not membrane associated, likely face the cytosol, and contain a motif that is implicated in interactions with ATP.
FATP1 is a member of a large family of related proteins from diverse organisms that increase fatty acid import when expressed in cultured cells (31). In mammalian organisms, FATP isoforms 1-5 have distinct tissue-specific distributions of expression. The importance of FATP proteins in LCFA transport is underscored by experiments in murine enterocytes in which antisense depletion of FATP4 significantly decreases LCFA import (59). Similarly, disruption of the yeast Saccharomyces cerevisiae FATP1 homolog fat1p results in impaired LCFA uptake and impaired growth under conditions in which de novo LCFA biosynthesis is inhibited and LCFAs are supplied as the sole carbon source (16, 18). Although no human diseases have been identified as resulting from FATP1 mutations, an intronic polymorphism in the FATP1 gene is associated with increased plasma triglyceride levels in women (47).
The second protein identified in this functional screen for proteins that facilitate import of LCFAs is long-chain acyl-CoA synthetase (ACS1). ACS1 catalyzes esterification of LCFAs (C14-C18) at the 1-C position with CoA (72), a required activation step for most anabolic and catabolic pathways in which fatty acids are used. The identification of ACS1 in the screen for proteins that increase LCFA uptake suggests that esterification of LCFAs is coupled with transport in mammalian cells. As has been proposed for LCFA import in E. coli, ACS may facilitate import through vectorial acylation. Consistent with this model, overexpression of FATP1 and ACS1 in fibroblasts has synergistic effects on LCFA uptake (21). Furthermore, ACS1 is an integral membrane protein that localizes to several cellular membranes of adipocytes, including the plasma membrane where it codistributes with FATP1.
Additional evidence for the importance of esterification in LCFA uptake in eukaryotes comes from experiments in yeast and in mice. Disruption of the yeast ACS1 orthologs FAA1 and FAA4 severely restricts uptake and metabolic utilization of exogenous fatty acids (12, 17). On the other hand, a transgenic mouse model of increased ACS1 expression in the heart (MHC-ACS) shows opposite results (11). MHC-ACS mice demonstrate marked cardiac myocyte triglyceride accumulation in the setting of a low-fat diet and normal serum lipid levels. Lipid accumulation in the heart results in initial cardiac hypertrophy, followed by the development of left ventricular dysfunction and premature death. This lipotoxic response to constitutive ACS overexpression underlines the importance of regulated cellular LCFA transport.
Although ACS1 is a well characterized enzyme that likely contributes to
LCFA uptake through vectorial acylation, the mechanism of action of
FATP1 is less clear. The observation of 40% amino acid sequence
identity between FATP1 and very long chain acyl-CoA synthetase (VLACS)
sequence has led to the hypothesis that this protein represents a
plasma membrane ACS with specificity for VLCFAs (70). The
homology between FATP1 and VLACS includes the 11-amino acid motif
(IYTSGTTGXPK) that is highly conserved in enzymes known or predicted to
form adenylated reaction intermediates, such as ACSs. FATP1 can be
specifically cross-linked to [-32P]azidoATP, and
mutations within this motif abrogate ATP binding and LCFA transport
(64, 65). Disruption of the yeast FATP1 ortholog fat1p
yields a strain with impaired LCFA import and utilization (18), normal long-chain ACS activity (18,
73), diminished VLACS activity, and increased concentrations of
free very long chain fatty acids (VLCFAs) (12, 16,
73). Studies in which overexpression of FATP1 in Cos7 cells
leads to increased VLACS activity that cofractionates with FATP1 also
suggest that FATP1 contains VLACS activity or closely associates with a
VLACS protein (15).
Taken together, these findings suggest that FATP1 has esterification activity. FATP1 may be a bifunctional molecule with separable transport and esterification activities (16). Alternatively, changes in the magnitude of LCFA uptake due to changes in FATP1 expression may more indirectly affect esterification. For example, disruption or overexpression of a gene encoding a protein in a metabolic pathway may result in compensatory metabolic changes in the cells. In particular, it is unclear whether some of the observed changes in VLACS activity are the result of alterations in the levels of LCFA ligands for peroxisome proliferator-activated receptors that, in turn, alter the level of expression of the peroxisomal enzyme VLACS. None of the studies to date examined purified protein outside the context in which metabolic compensations are likely to occur. Moreover, there remain unresolved discrepancies in substrate specificity. FATP1 facilitates import of LCFAs and VLCFAs, whereas known VLACS enzymes have no activity toward long-chain substrates.
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ARE ANY OF THESE PROTEINS TRANSPORTERS? |
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Whether CD36, FABPpm, and FATP1 function as transporters for LCFAs
remains to be established. Although functional studies suggest that
these proteins play a role in LCFA import in mammalian cells, several
questions remain. First, the membrane topology for each of these
proteins does not resemble that of polytopic membrane
transporters for hydrophilic substrates. Many transporters are
predicted to have transmembrane domains (4-12 per transporter) consisting primarily of -helical structures of 17 or more amino acids that span the phospholipid bilayer. The transmembrane domains of
well characterized transporters are thought to form a three-dimensional channel through which substrate passes. Second, gain and loss of
function studies are potentially confounded by cellular metabolic compensations. Third, tight coupling of transport and esterification renders measurements of transport alone difficult. Fourth, loss of
function studies may be complicated by compensatory upregulation of
expression of other highly related protein family members.
A number of studies have reported changes in patterns of expression of FATP, FAT, and FABPpm at the level of mRNA (Northern blot) or protein (Western blot) abundance in homogenates of whole tissue. Changes in expression of the various proteins in experimental or pathophysiological states that correlate with changes in the magnitude of LCFA transport are consistent with an important role of these proteins in regulating fatty acid import (6, 23, 46, 48, 49, 71). However, lack of expected changes in mRNA or protein abundance in a total cellular lysate (as shown in Ref. 44) cannot be taken as proof that a particular protein is irrelevant to LCFA import. Such methods may fail to detect changes in posttranslational modification, protein half-life, or subcellular localization. Indeed, recent studies indicate that subcellular localization of CD36 may play an important role in regulation of fatty acid uptake in contracting skeletal muscle (10).
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CONCLUSIONS |
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Experimental evidence exists for both flip-flop and
protein-mediated LCFA permeation (Fig.
1). Although flip-flop of nonionized LCFAs is sufficiently rapid to allow LCFA uptake, such a mechanism may
facilitate LCFA uptake primarily in settings of high extracellular free
LCFA concentrations. In vertebrate organisms, free LCFAs are generated
by lipase-mediated hydrolysis of triglycerides in adipose stores or by
hydrolysis of triglycerides from lipoprotein particles in plasma.
Within serum, free LCFAs are largely bound to albumin, resulting in low
nanomolar concentrations (mean 7.5 nm) of free unbound fatty acids
under normal physiological conditions (53). In
pathophysiological states, however, LCFA/BSA ratios as high as 7.1 have
been observed, with corresponding concentrations of unbound free fatty
acids of 550 nm (39). Under such conditions, membrane
permeation of nonionized LCFAs may not be facilitated by proteins but
rather occur by flip-flop.
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On the other hand, proteins are likely to play an important role in LCFA import in settings in which LCFAs are ionized and in which FA/BSA ratios of <3.0 result in low unbound LCFA concentrations. Under such conditions, plasma membrane albumin receptors may facilitate LCFA dissociation to increase local concentrations of LCFAs at the extracellular face of the membrane. In eukaryotes, proteins such as FABPpm, CD36, or FATPs may contribute to the permeation step or its regulation. Changes in expression or function of such proteins may orchestrate the observed developmental and pathophysiological regulation of LCFA utilization in accordance with nutritional and hormonal signals. The mechanism of action of these proteins is not well understood and is the subject of ongoing investigations by a number of groups.
Regardless of the mechanism employed for membrane permeation, studies from diverse organisms provide compelling evidence that esterification of imported LCFAs plays an important role in LCFA import. The enzymes that catalyze esterification may affect both the rate and directionality of LCFA movement across membranes. These enzymes may be physically as well as functionally coupled to other proteins that participate in LCFA import as constituents in cell surface transport complexes. Or these enzymes may function at the inner leaflet of the membrane in concert with permeation by flip-flop. In the absence of esterification at the inner leaflet, LCFA permeation may be bidirectional. For cells that demonstrate efficient LCFA efflux as well as influx, regulation of expression, localization, or activity of esterification enzymes may be required to facilitate bidirectional movement of LCFAs in response to appropriate stimuli.
Because of the physiological significance of regulated LCFA flux in
vivo, understanding the mechanism of action of proteins implicated in
LCFA uptake is an important goal. Once transported across the membrane
of parenchymal cells, LCFAs are targeted to specific metabolic fates.
Under normal conditions, adipocytes have the capacity to store excess
LCFAs as triglyceride in lipid droplets, whereas nonadipose cells
generally achieve a balance between fatty acid uptake and utilization.
In pathophysiological states such as non-insulin-dependent diabetes
mellitus (NIDDM), high serum levels of LCFAs may contribute to
high-level LCFA import in excess of cellular needs for these molecules
(41, 58). Evidence is emerging that accumulation of fatty
acids in skeletal muscle and pancreatic -cells leads to insulin
resistance and abnormal insulin secretion, respectively (24, 43,
56). Furthermore, in several animal models, increased fatty acid
import into pancreatic
-cells and cardiac myocytes leads to
accumulation of triglycerides, induction of programmed cell death, and
organ dysfunction manifested as diabetes (57) and heart
failure (11, 77). Thus the mechanism of LCFA import and
the manner in which it is regulated have relevance to common human
diseases. Understanding the mechanism of LCFA permeation may contribute
to the design of novel therapies to treat NIDDM or heart failure.
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ACKNOWLEDGEMENTS |
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I thank D. Ory and L. Listenberger for helpful comments.
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FOOTNOTES |
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This work was supported by grants from the National Institutes of Health (DK-54268 and HL-61006).
Address for reprint requests and other correspondence: J. Schaffer, Depts. of Internal Medicine, Molecular Biology, and Pharmacology, Washington Univ. School of Medicine, St. Louis, MO 63110 (E-mail: Jschaff{at}im.wustl.edu).
10.1152/ajpendo.00462.2001
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