Reference Work Entry

Encyclopedia of Cancer

pp 1383-1386

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Fatty Acid Transport

Definition

Is the process through which free fatty acids pass through the membranes of cells. The term may include: uptake of fatty acids from the blood or the extracellular space; release of fatty acids from the cell interior to the extracellular space or blood; and transport of fatty acids within the cell across intracellular membranes during biosynthesis and metabolism. While all three types of transport may occur in tumor cells, this entry concentrates on the characteristics and mechanisms for free fatty acid entry into tumor cells.

Characteristics

Fatty acids serve multiple functions in cells and their transport from arterial blood plasma to the cell interior is necessary for cell growth and survival. Fatty acid oxidation is a major source of energy for heat production and generation of ATP for biosynthesis and growth. During metabolism fatty acids are incorporated into several complex lipids required for cell structure and function. Fatty acids also play important roles in cell signaling; they are anchors for attachment of specific signaling proteins to membranes and they are converted to several types of lipid mediators involved in intra- and extracellular cell signaling mechanisms. The essential long-chain polyunsaturated fatty acids, linoleic (C18:2n6), linolenic (C18:3n3), eicosapentaenoic (C20:5n3), and docosahexaenoic (C22:6n3) acids, which are obtained from dietary sources, play particularly important roles in cell signaling, membrane structure, growth and control of fatty acid transport. If dietary fat consumption exceeds the need, fatty acids are stored in white adipose tissue as triacylglycerols for subsequent release during postprandial and longer periods of food deprivation.

Fatty acids greater than eight carbons in chain length are not very water soluble and are transported in the blood bound to plasma albumin. The plasma albumin–fatty acid pool is maintained by release of free fatty acids from plasma lipoproteins (catalyzed by endothelial lipoprotein lipase) and by release of free fatty acids from lipid stores. Fatty acids bound to plasma albumin dissociate from the albumin binding sites to maintain a plasma free fatty acid concentration of 7–10 nM. This plasma free fatty acid pool is a major source of free fatty acids for cell consumption. Accumulation of high free fatty acid concentrations inside cells, however, is toxic for cell structure and function and specific intracellular fatty acid binding proteins (FABPs) are present in cells to maintain low free fatty acid concentrations. Specific isoforms of these FABPs are expressed in different organs and tissues.

Characteristics: Tumor

Transplantable solid rodent tumors and human cancer xenografts grown in nude rats have ready access to the free fatty acid pool in arterial blood plasma. Cancers that arise spontaneously undoubtedly also have access to plasma fatty acids. Arteriovenous difference measurements in arterial and tumor venous blood plasma samples collected across solid tumors in vivo or during perfusion in situ indicate that substantial rates of fatty acid uptake occur. Thirty-five to 45% of the total fatty acids in arterial blood plasma is removed during one pass of the arterial blood through a fast-growing rat hepatoma. Similar uptakes (35–45%) occur for each of the seven major plasma fatty acids in rat arterial blood: myristic, palmitic, palmitoleic, stearic, oleic, linoleic, and arachidonic acids. Consequently, larger amounts of the more abundant plasma fatty acids, oleic, linoleic, and arachidonic acids are removed. Since tumor fatty acid uptake is proportional to the arterial plasma fatty content of each fatty acid, there is no preferential uptake of any single fatty acid. Each of five different human cancer xenografts, ER+ and ER MCF-7 breast, PC3 prostate, CFDT1 renal transitional and FaDu pharyngeal carcinomas, grown in nude rats removes fatty acids from the arterial blood plasma. Fatty acid uptake by human tumors also occurs in proportion to the concentration of the individual fatty acid in arterial blood plasma. However, the rates and efficiencies of fatty acid uptake in human cancer xenografts are different and are directly proportional to the tumor growth rate.

Growth and incorporation of [3H]thymidine into DNA in rodent tumors and human cancer xenografts in vivo or during perfusion in situ are directly dependent on the availability and uptake of plasma linoleic acid. Plasma linoleic acid concentrations, tumor linoleic acid uptakes, and growth rates are increased in tumor-bearing rats fed diets enriched in linoleic acid. Similar stimulations of tumor growth occur when tumor-bearing rats are subjected to an acute fast, except that the elevation in plasma linoleic acid content in the acutely fasted rats is derived from lipolysis of host fat stores. In contrast, the absence of linoleic acid in arterial blood plasma, as occurs in tumor-bearing rats fed a linoleic acid-deficient diet, inhibits growth and the rate of [3H]thymidine incorporation into tumor DNA. Linoleic acid–dependent growth in rodent tumors and human cancer xenografts results from the conversion in the tumor of linoleic acid to 13-hydroxyoctadecadienoic acid (13-HODE). 13-HODE, a mitogen in these tumors, is a product of lipoxygenase activity and is released into the tumor venous blood plasma. Depending on the tumor type, 1–10% of the linoleic acid removed from the arterial blood is converted to 13-HODE. Thus, tumor growth rates are directly proportional to both linoleic acid uptake and 13-HODE release.

Arterial blood plasma long-chain polyunsaturated fatty acids affect tumor growth differently; whereas the n6 fatty acid, linoleic acid, increases tumor growth, the presence of n3 fatty acids in arterial blood plasma inhibits tumor growth. In tumor-bearing rats fed a diet containing both linoleic acid and n3 fatty acids, the rates of linoleic acid uptake, 13-HODE production, [3H]thymidine incorporation into DNA and growth are suppressed. Each of the n3 fatty acids, α-linolenic, stearidonic, eicosapentaenoic, and docosahexaenoic acids, inhibits fatty acid transport; a 50% inhibition occurs at a plasma n3 fatty acid concentration of about 0.15 mM. Most interesting, uptake of all plasma saturated, monounsaturated, and n6 polyunsaturated fatty acids is depressed by n3 fatty acids. However, tumor uptake of n3 fatty acids is not inhibited. Other dietary agents also inhibit tumor fatty acid transport and growth. These include melatonin and some conjugated linoleic acid isomers and trans fatty acids. As with n3 fatty acids, the inhibition of tumor fatty acid transport is directly proportional to the arterial blood plasma content of the inhibitor. Melatonin, which is present in the diet and is the natural hormone of the pineal gland, is the most potent inhibitor of tumor fatty acid transport yet discovered. A plasma concentration of 0.1 nM melatonin causes a 50% inhibition of fatty acid transport. In addition to inhibitions of both fatty acid transport and 13-HODE release, these agents cause significant reductions in the intratumor cAMP content, [3H]thymidine incorporation, and phosphorylated-MEK and -ERK1/2 (MAP Kinase). Significantly, these inhibitions caused by n3 fatty acids, melatonin, CLA isomers, and trans fatty acids are reversed by the addition of either 8-bromo-cAMP or pertussis toxin to the arterial blood containing these agents. (Pertussis toxin catalyzes the ADP-ribosylation of the α subunit of inhibitory heteromeric guanine nucleotide G proteins and reactivates the inhibited adenylyl cyclase activity. 8-bromo-cAMP is a cell-permeable analog of cAMP that is resistant to hydrolysis by phosphodiesterases.) Addition of 13-HODE to the arterial blood restores phosphorylated-MEK and -ERK1/2 and [3H]thymidine incorporation but not fatty acid transport. The results strongly suggest that fatty acid transport and growth in rodent tumors and human cancers are dependent on an elevated intratumor cAMP content and that the inhibition of fatty acid transport is mediated by an inhibitory G protein-coupled receptor(s).

Mechanisms

The mechanism for fatty acid transport in eukaryotic cells is not yet clearly resolved. Two hypotheses, transport by passive diffusion and transport by protein-mediated carriers, have been presented and studied extensively in model membrane vesicles and cultured cells. Lipophilic nonionized free fatty acids rapidly penetrate membrane vesicles and red cells, a process that has been termed flip-flop to describe movement of the fatty acid across the membrane leaflet barrier. The barrier to flip-flop is increased by ionization of the fatty acid and may be further increased by changes in the lipid phases in cell membranes of different cells. These findings strengthen the hypothesis for fatty acid transport via protein-mediated carriers. Three groups of membrane protein carriers that contribute to fatty acid transport have been identified in mammalian cells. Fatty acid transport proteins (FATP1–6) are a family of proteins that have distinct tissue distributions. Several but not all of the FATP isoforms transport fatty acids across cell membranes; several also have long-chain fatty acid Co-A synthetase (LCACS) activity, which may be important for retention of the fatty acid inside the cell. Evidence also indicates that the plasma membrane protein fatty acid translocase (FAT/CD36) is involved in fatty acid uptake in heart, skeletal muscle, and adipose tissue. Control of fatty acid transport by FATP isoforms and FAT/CD36 may involve movement of the carriers between intracellular membranes and the plasma membrane. A fatty acid binding protein in plasma membranes (FABPpm) that is present in heart, intestine, liver, and adipocytes may also play an important role in fatty acid transport. Since all of these proteins may be present in cells, cooperative activities (as yet undefined) may occur among the different protein carriers.

The requirement for high intratumor cAMP is a unique property that appears to control fatty acid transport in solid tumors. The mechanisms that maintain the high intratumor cAMP content are not known but may be catalyzed by stimulatory GsPCR(s) (G Proteins). This cAMP requirement is not easily reconcilable with the current understanding of fatty acid transport mediated by either passive diffusion or by protein carriers. Depletion of intratumor cAMP and inhibition of fatty acid transport caused by n3 fatty acids, melatonin, or CLA isomers is dose-dependent and complete at high inhibitor concentrations. Despite the fact that arterial blood plasma fatty acid concentrations remain available to the tumor, fatty acid transport into the tumor is inhibited. However, addition of either 8-bromo-cAMP or pertussis toxin to the inhibitor-containing arterial blood restores intratumor cAMP and fatty acid transport. Reversal of the inhibition by these agents indicates that inhibitory GiPCR(s) (G Proteins) for n3 fatty acid, melatonin, and CLA isomers mediate the reduction of intratumor cAMP and inhibition of fatty acid transport. Rat hepatoma 7288CTC and the human cancer xenografts contain one or both of the inhibitory G protein-coupled melatonin receptors, MT1 and MT2. Compound S20928, a specific antagonist for melatonin receptors MT1 and MT2, increases intratumor cAMP and mitigates the melatonin inhibition. There is as yet no direct evidence that inhibitory G protein-coupled receptors for n3 fatty acids, CLA isomers, or trans fatty acids exist in solid tumors. mRNA for FATP1 is overexpressed in a rat hepatoma suggesting that FATP1 may mediate fatty acid transport in hepatomas and other tumors. If that is the case, the activity of FATP1 as a fatty acid transport carrier in these tumors may require cAMP (Fig. 1).
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Fatty Acid Transport. Fig. 1

Schematic representations for fatty acid transport (a) and control of transport (b) by dietary inhibitors. (a) The sequence of events associated with elevated intratumor cAMP, uptake of linoleic acid, 13-HODE production, and cell proliferation is designated by solid arrows. (b) Attenuation of intratumor cAMP and fatty acid transport caused by binding of n3 fatty acids, melatonin, CLA isomers, or trans fatty acids to inhibitory G protein-coupled receptors is designated by dashed arrows. Abbreviations are: G i PCR inhibitory G protein-coupled receptors, G s PCR stimulatory G protein-coupled receptor, 13-HODE 13-hydroxyoctadecadienoic acid, LCACS long chain fatty acid acyl-Co A synthetase, LIPOX lipoxygenase, LA linoleic acid, PKA protein kinase A

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