scholarly journals New insights into long-chain fatty acid uptake by heart muscle: a crucial role for fatty acid translocase/CD36

2002 ◽  
Vol 367 (3) ◽  
pp. 561-570 ◽  
Author(s):  
Joep F.F. BRINKMANN ◽  
Nada A. ABUMRAD ◽  
Azeddine IBRAHIMI ◽  
Ger J. vanderVUSSE ◽  
Jan F.C. GLATZ
Keyword(s):  
Plasma Membrane ◽  
Fatty Acid ◽  
Heart Muscle ◽  
Fatty Acid Transport ◽  
Acid Uptake ◽  
Membrane Fatty Acid ◽  
Acid Transport ◽  
Fatty Acid Binding ◽  
Fatty Acid Translocase ◽  
Long Chain

Long-chain fatty acids are an important source of energy for several cell types, in particular for the heart muscle cell. Three different proteins, fatty acid translocase (FAT)/CD36, fatty acid transport protein and plasma membrane fatty acid binding protein, have been identified as possible membrane fatty acid transporters. Much information has been accumulated recently about the fatty acid transporting function of FAT/CD36. Several experimental models to study the influence of altered FAT/CD36 expression on fatty acid homoeostasis have been identified or developed, and underscore the importance of FAT/CD36 for adequate fatty acid transport. These models include the FAT/CD36 null mouse, the spontaneously hypertensive rat and FAT/CD36-deficient humans. The fatty acid transporting role of FAT/CD36 is further demonstrated in mice overexpressing muscle-specific FAT/CD36, and in transgenic mice generated using a genetic-rescue approach. In addition, a wealth of information has been gathered about the mechanisms that regulate FAT/CD36 gene expression and the presence of functional FAT/CD36 on the plasma membrane. Available data also indicate that FAT/CD36 may have an important role in the aetiology of cardiac disease, especially cardiac hypertrophy and diabetic cardiomyopathy. This review discusses our current knowledge of the three candidate fatty acid transporters, the metabolic consequences of alterations in FAT/CD36 levels in different models, and the mechanisms that have been identified for FAT/CD36 regulation.

Protein-mediated fatty acid uptake: regulation by contraction, AMP-activated protein kinase, and endocrine signals

2007 ◽  
Vol 32 (5) ◽  
pp. 865-873 ◽  
Author(s):  
James G. Nickerson ◽  
Iman Momken ◽  
Carley R. Benton ◽  
James Lally ◽  
Graham P. Holloway ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Acid Oxidation ◽  
Fatty Acid Transport ◽  
Acid Uptake ◽  
Acid Transport ◽  
Fatty Acid Binding ◽  
Mitochondrial Fatty Acid ◽  
Amp Activated Protein Kinase

Fatty acid transport into heart and skeletal muscle occurs largely through a highly regulated protein-mediated mechanism involving a number of fatty acid transporters. Chronically altered muscle activity (chronic muscle stimulation, denervation) alters fatty acid transport by altering the expression of fatty acid transporters and (or) their subcellular location. Chronic exposure to leptin downregulates while insulin upregulates fatty acid transport by altering concomitantly the expression of fatty acid transporters. Fatty acid transport can also be regulated within minutes, by muscle contraction, AMP-activated protein kinase activation, leptin, and insulin, through induction of the translocation of fatty acid translocase (FAT)/CD36 from its intracellular depot to the plasma membrane. In insulin-resistant muscle, a permanent relocation of FAT/CD36 to the sarcolemma appears to account for the excess accretion of intracellular lipids that interfere with insulin signaling. Recent work has also shown that FAT/ CD36, but not plasma membrane associated fatty acid binding protein, is involved, along with carnitine palmitoyltransferase, in regulating mitochondrial fatty acid oxidation. Finally, studies in FAT/CD36 null mice indicate that this transporter has a key role in regulating fatty acid metabolism in muscle.

Changes in fatty acid transport and transporters are related to the severity of insulin deficiency

2002 ◽  
Vol 283 (3) ◽  
pp. E612-E621 ◽  
Author(s):  
Joost J. F. P. Luiken ◽  
Yoga Arumugam ◽  
Rhonda C. Bell ◽  
Jorge Calles-Escandon ◽  
Narendra N. Tandon ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Plasma Membrane ◽  
Fatty Acid ◽  
Fatty Acid Transport ◽  
Acid Uptake ◽  
Acid Transport ◽  
Fatty Acid Binding ◽  
Fatty Acid Transporter ◽  
Acid Transporter

We have examined the effects of streptozotocin (STZ)-induced diabetes (moderate and severe) on fatty acid transport and fatty acid transporter (FAT/CD36) and plasma membrane-bound fatty acid binding protein (FABPpm) expression, at the mRNA and protein level, as well as their plasmalemmal localization. These studies have shown that, with STZ-induced diabetes, 1) fatty acid transport across the plasma membrane is increased in heart, skeletal muscle, and adipose tissue and is reduced in liver; 2) changes in fatty acid transport are generally not associated with changes in fatty acid transporter mRNAs, except in the heart; 3) increases in fatty acid transport in heart and skeletal muscle occurred with concomitant increases in plasma membrane FAT/CD36, whereas in contrast, the increase and decrease in fatty acid transport in adipose tissue and liver, respectively, were accompanied by concomitant increments and reductions in plasma membrane FABPpm; and finally, 4) the increases in plasma membrane transporters (FAT/CD36 in heart and skeletal muscle; FABPpm in adipose tissue) were attributable to their increased expression, whereas in liver, the reduced plasma membrane FABPpm appeared to be due to its relocation within the cell in the face of slightly increased expression. Taken together, STZ-induced changes in fatty acid uptake demonstrate a complex and tissue-specific pattern, involving different fatty acid transporters in different tissues, in combination with different underlying mechanisms to alter their surface abundance.

Effect of surface and intracellular pH on hepatocellular fatty acid uptake

1996 ◽  
Vol 271 (6) ◽  
pp. G1067-G1073
Author(s):  
C. Elsing ◽  
A. Kassner ◽  
W. Stremmel
Keyword(s):  
Fatty Acids ◽  
Plasma Membrane ◽  
Fatty Acid ◽  
Intracellular Ph ◽  
Outer Surface ◽  
Fatty Acid Uptake ◽  
Proton Gradient ◽  
Fatty Acid Transport ◽  
Acid Uptake ◽  
Acid Transport

Fatty acids enter hepatocytes, at least in part, by a carrier-mediated uptake mechanism. The importance of driving forces for fatty acid uptake is still controversial. To evaluate possible driving mechanisms for fatty acid transport across plasma membranes, we examined the role of transmembrane proton gradients on fatty acid influx in primary cultured rat hepatocytes. After hepatocytes were loaded with SNARF-1 acetoxymethyl ester, changes in intracellular pH (pHi) under different experimental conditions were measured and recorded by confocal laser scanning microscopy. Fatty acid transport was increased by 45% during cellular alkalosis, achieved by adding 20 mM NH4Cl to the medium, and a concomitant paracellular acidification was observed. Fatty acid uptake was decreased by 30% during cellular acidosis after withdrawal of NH4Cl from the medium. Cellular acidosis activates the Na+/H+ antiporter to export excessive protons to the outer cell surface. Inhibition of Na+/H+ antiporter activity by amiloride diminishes pHi recovery and thereby accumulation of protons at the outer surface of the plasma membrane. Under these conditions, fatty acid uptake was further inhibited by 57% of control conditions. This suggests stimulation of fatty acid influx by an inwardly directed proton gradient. The accelerating effect of protons at the outer surface of the plasma membrane was confirmed by studies in which pH of the medium was varied at constant pHi. Significantly higher fatty acid influx rates were observed at low buffer pH. Recorded differences in fatty acid uptake appeared to be independent of changes in membrane potential, because BaCl2 did not influence initial uptake velocity during cellular alkalosis and paracellular acidosis. Moreover, addition of oleate-albumin mixtures to the NH4Cl incubation buffer did not change the observed intracellular alkalinization. In contrast, after cells were acid loaded, addition of oleate-albumin solutions to the recovery buffer increased pHi recovery rates from 0.21 +/- 0.02 to 0.36 +/- 0.05 pH units/min (P < 0.05), indicating that fatty acids further stimulate Na+/H+ antiporter activity during pHi recovery from an acid load. It is concluded that carrier-mediated uptake of fatty acids in hepatocytes follows an inwardly directed transmembrane proton gradient and is stimulated by the presence of H+ at the outer surface of the plasma membrane.

Stopped-flow kinetic analysis of long-chain fatty acid dissociation from bovine serum albumin

2002 ◽  
Vol 363 (3) ◽  
pp. 809-815 ◽  
Author(s):  
Erland J.F. DEMANT ◽  
Gary V. RICHIERI ◽  
Alan M. KLEINFELD
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Time Course ◽  
Acid Dissociation ◽  
Fatty Acid Transport ◽  
Acid Transport ◽  
Fatty Acid Binding ◽  
Kinetics Of ◽  
Initial Fatty Acid ◽  
Long Chain

The kinetics of the interaction of long-chain fatty acids (referred to as fatty acids) with albumin is critical to understanding the role of albumin in fatty acid transport. In this study we have determined the kinetics of fatty acid dissociation from BSA and the BSA-related fatty acid probe BSA-HCA (BSA labelled with 7-hydroxycoumarin-4-acetic acid) by stopped-flow methods. Fatty acid—albumin complexes of a range of natural fatty acid types and albumin molecules (donors) were mixed with three fatty acid-binding acceptor proteins. Dissociation of fatty acids from the donor was monitored by either the time course of donor fluorescence/absorbance or the time course of acceptor fluorescence. The results of these measurements indicate that fatty acid dissociation from BSA as well as BSA-HCA is well described by a single exponential function over the entire range of fatty acid/albumin molar ratios used in these measurements, from 0.5:1 to 6:1. The observed rate constants (kobs) for the dissociation of each fatty acid type reveal little or no dependence on the initial fatty acid/albumin ratio. However, dissociation rates were dependent upon the type of fatty acid. In the case of native BSA with an initial fatty acid/BSA molar ratio of 3:1, the order of kobs values was stearic acid (1.5s−1)<oleic acid<palmitic acid≅linoleic acid<arachidonic acid (8s−1) at 37°C. The corresponding values for BSA-HCA were about half the values for BSA. The results of this study show that the rate of fatty acid dissociation from native BSA is more than 10-fold faster than reported previously and that the off-rate constants for the five primary fatty acid-binding sites differ by less than a factor of 2. We conclude that for reported rates of fatty acid transport across cell membranes, dissociation of fatty acids from the fatty acid—BSA complexes used in the transport studies should not be rate-limiting.

scholarly journals Constitutive expression of a saturable transport system for non-esterified fatty acids in Xenopus laevis oocytes

1994 ◽  
Vol 297 (2) ◽  
pp. 315-319 ◽  
Author(s):  
S L Zhou ◽  
D Stump ◽  
L Isola ◽  
P D Berk
Keyword(s):  
Fatty Acids ◽  
Plasma Membrane ◽  
Fatty Acid ◽  
Fatty Acid Binding Protein ◽  
Xenopus Laevis Oocytes ◽  
Long Chain Fatty Acids ◽  
Membrane Fatty Acid ◽  
Fatty Acid Binding ◽  
Acid Binding Protein ◽  
Long Chain

In the presence of 150 microM BSA, uptake of [3H]oleate by Xenopus laevis oocytes was a saturable function of the unbound oleate concentration (Vmax. 110 +/- 4 pmol/h per oocyte; Km 193 +/- 11 nM unbound oleate). Oleate uptake was three orders of magnitude faster than that of another test substance, [35S]bromosulphophthalein, and was competitively inhibited by 55 nM unbound palmitate (Vmax. 111 +/- 14 pmol/h per oocyte; Km 424 +/- 63 nM unbound oleate) (P < 0.01). Oleate uptake was also inhibited by antibodies to a 43 kDa rat liver plasma-membrane fatty acid-binding protein, a putative transporter of long-chain fatty acids in mammalian cells; uptake of the medium-chain fatty acid [14C]octanoate was unaffected. Immunofluorescence and immunoblotting demonstrated that the antiserum reacted with a single 43 kDa protein on the oocyte surface. Hence a protein related to the mammalian plasma-membrane fatty acid-binding protein may play a role in saturable uptake of long-chain fatty acids by Xenopus oocytes.

Common mechanisms of monoacylglycerol and fatty acid uptake by human intestinal Caco-2 cells

2001 ◽  
Vol 281 (4) ◽  
pp. C1106-C1117 ◽  
Author(s):  
Shiu-Ying Ho ◽  
Judith Storch
Keyword(s):  
Plasma Membrane ◽  
Fatty Acid ◽  
Monomer Concentration ◽  
Protein S ◽  
Fatty Acid Uptake ◽  
Fatty Acid Transport ◽  
Acid Uptake ◽  
Fatty Acid Binding ◽  
Bound Lipids ◽  
Kinetics Of

Free fatty acids (FFA) and sn-2-monoacylglycerol ( sn-2-MG), the two hydrolysis products of dietary triacylglycerol, are absorbed from the lumen into polarized enterocytes that line the small intestine. Intensive studies regarding FFA transport across the brush-border membrane of the enterocyte are available; however, little is known about sn-2-MG transport. We therefore studied the kinetics of sn-2-MG transport, compared with those of long-chain FFA (LCFA), by human intestinal Caco-2 cells. To mimic postprandial luminal and plasma environments, we examined the uptake of taurocholate-mixed lipids and albumin-bound lipids at the apical (AP) and basolateral (BL) surfaces of Caco-2 cells, respectively. The results demonstrate that the uptake of sn-2-monoolein at both the AP and BL membranes appears to be a saturable function of the monomer concentration of sn-2-monoolein. Furthermore, trypsin preincubation inhibits sn-2-monoolein uptake at both AP and BL poles of cells. These results suggest that sn-2-monoolein uptake may be a protein-mediated process. Competition studies also support a protein-mediated mechanism and indicate that LCFA and LCMG may compete through the same membrane protein(s) at the AP surface of Caco-2 cells. The plasma membrane fatty acid-binding protein (FABPpm) is known to be expressed in Caco-2, and here we demonstrate that fatty acid transport protein (FATP) is also expressed. These putative plasma membrane LCFA transporters may be involved in the uptake of sn-2-monoolein into Caco-2 cells.

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