Oligomerization of the Murine Fatty Acid Transport Protein 1

Richards, Mark; Listenberger, Laura L.; Kelly, Alicia A.; Lewis, Sarah; Ory, Daniel S.; Schaffer, Jean E.

doi:10.1074/jbc.m212469200

Cited by 36 publications

(34 citation statements)

References 26 publications

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“…Previously, we published results indicating that FATP1 homodimerization plays a role in fatty acid uptake function (19). In this study, we observed coimmunoprecipitation between differently epitope-tagged forms of FATP1 and ACSL1 in 3T3-L1 adipocytes.…”

Section: Discussionsupporting

confidence: 59%

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Fatty acid transport protein 1 and long-chain acyl coenzyme A synthetase 1 interact in adipocytes

Richards

Harp

Ory

et al. 2006

Journal of Lipid Research

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102

103

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The fatty acid transport proteins (FATP) and longchain acyl coenzyme A synthetase (ACSL) proteins have been shown to play a role in facilitating long-chain fatty acid (LCFA) transport in mammalian cells under physiologic conditions. The involvement of both FATP and ACSL proteins is consistent with the model of vectorial acylation, in which fatty acid transport is coupled to esterification. This study was undertaken to determine whether the functions of these proteins are coordinated through a protein-protein interaction that might serve as a point of regulation for cellular fatty acid transport. We demonstrate for the first time that FATP1 and ACSL1 coimmunoprecipitate in 3T3-L1 adipocytes, indicating that these proteins form an oligomeric complex. The efficiency of FATP1 and ACSL1 coimmunoprecipitation is unaltered by acute insulin treatment, which stimulates fatty acid uptake, or by treatment with isoproterenol, which decreases fatty acid uptake and stimulates lipolysis. Moreover, inhibition of ACSL1 activity in adipocytes impairs fatty acid uptake, suggesting that esterification is essential for fatty acid transport. Together, our findings suggest that a constitutive interaction between FATP1 and ACSL1 contributes to the efficient cellular uptake of LCFAs in adipocytes through vectorial acylation. A central aspect of adipocyte biology is the ability of these specialized cells to efficiently take up and store longchain fatty acids (LCFAs) in response to nutritional and hormonal cues. In the "fed" state, higher serum levels of insulin stimulate an increase in fatty acid uptake and triglyceride storage in adipose tissue. On the other hand, during "starvation," b-adrenergic receptor agonists, such as epinephrine, stimulate pathways that activate hormonesensitive lipase in adipocytes, resulting in the hydrolysis of triglycerides and the release of free fatty acids and glycerol. In obesity and the metabolic syndrome, dysregulation of these processes may contribute to increases in serum free fatty acids and the genesis of type 2 diabetes (1, 2).The movement of LCFAs across the plasma membrane is tightly coupled to thioesterification, a process referred to as vectorial acylation (3). Early evidence for this mechanism came from genetic studies of Escherichia coli, in which fatty acid transport requires FadL, an outer membrane LCFA transporter, and FadD, an inner membraneassociated acyl CoA synthetase (4, 5). Vectorial acylation provides cells with an efficient means of rapidly metabolizing incoming fatty acids and contributes to decreasing the intracellular concentration of free fatty acids to favor import. Thioesterification of LCFAs is also an essential initial metabolic step for many downstream metabolic pathways of LCFA use, such as b-oxidation or triglyceride synthesis. The coupled transport and metabolism of LCFAs is analogous to glucose transport in mammalian cells, a process in which GLUT4-mediated translocation of glucose across the plasma membrane is coordinated with rapid phosphorylation by hexokin...

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Section: Discussionsupporting

confidence: 59%

“…Previously, we showed that FATP1 forms homodimers and that dimerization plays a functional role in cellular fatty acid import (19). Thus, we tested whether ACSL1 forms an oligomeric complex with more than one molecule of FATP1.…”

Section: Fatp1 and Acsl1 Coimmunoprecipitate In 3t3-l1 Adipocytesmentioning

confidence: 99%

Fatty acid transport protein 1 and long-chain acyl coenzyme A synthetase 1 interact in adipocytes

Richards

Harp

Ory

et al. 2006

Journal of Lipid Research

Self Cite

102

103

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“…These data are consistent with the proposal that this motif contributes to fatty acid transport. Several FATPs are localized, at least in part, to the plasma membrane further supporting their functional role in fatty acid transport [7,9,11,[23][24][25]. The transmembrane domains within the FATPs are amino-terminal proximal; one transmembrane domain has been identified in FATP1 [23] while two have been identified in Fat1p [26].…”

Section: Introductionmentioning

confidence: 95%

Functional domains of the fatty acid transport proteins: Studies using protein chimeras

DiRusso

Darwis

Obermeyer

et al. 2008

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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SUMMARYFatty acid transport proteins (FATP) function in fatty acid trafficking pathways, several of which have been shown to participate in the transport of exogenous fatty acids into the cell. Members of this protein family also function as acyl CoA synthetases with specificity towards very long chain fatty acids or bile acids. These proteins have two identifying sequence motifs: The ATP/AMP motif, an approximately 100 amino acid segment required for ATP binding and common to members of the adenylate-forming super family of proteins, and the FATP/VLACS motif that consists of approximately 50 amino acid residues and is restricted to members of the FATP family. This latter motif has been implicated in fatty acid transport in the yeast FATP orthologue Fat1p. In the present studies using a yeast strain containing deletions in FAT1 (encoding Fat1p) and FAA1 (encoding the major acyl CoA synthetase (Acsl) Faa1p) as an experimental platform, the phenotypic and functional properties of specific murine FATP1-FATP4 and FATP6-FATP4 protein chimeras were evaluated in order to define elements within these proteins that further distinguish the fatty acid transport and activation functions. As expected from previous work FATP1 and FATP4 were functional in the fatty acid transport pathway, while and FATP6 was not. All three isoforms were able to activate the very long chain fatty acids arachidonate (C 20:4 ) and lignocerate (C 24:0 ), but with distinguishing activities between saturated and highly unsaturated ligands. A 73 amino acid segment common to FATP1 and FATP4 and between the ATP/AMP and FATP/VLACS motifs was identified by studying the chimeras, which is hypothesized to contribute to the transport function.

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“…Whereas it is highly speculative that the first 185 amino acids encoded by exons 1 and 2 would present a peptide with biological activity, it is worthwhile noting that this region is homologous to fragments of FATP1 that would include the entire extracellular N terminus, the transmembrane region, and cytoplasmic membraneassociated sequences (38). Because FATPs may be multifunctional proteins with separable residues involved in LCFA transport and activation (39), the hypothetical fusion proteins could retain some aspects of FATP4 function, such as LCFA transport, or interaction with other proteins, for instance longchain acyl-CoA synthetases (40) or other FATPs (19). Although the causes of neonatal mortality, described by Moulson et al (30) and Herrmann et al (22), may differ from the embryonic death described in this article, both lethalities ultimately underscore the importance of FATP4-mediated LCFA uptake/ activation for normal physiology.…”

Section: Table IIImentioning

confidence: 99%

“…The AMP-binding motive in FATP1 mediates ATP binding and is required for LCFA uptake, since mutations within this motif abolish uptake activity (17,18). Oligomerization also seems to be required for transport function, because co-expression of non-functional FATP1 mutants with wild-type FATP1 resulted in dominant negative inhibition of transport (19). Based on the finding that both long-chain and very long-chain acyl-CoA synthetase activities are increased in lysates from FATP overexpressing cells (20) and in partially purified FATP1 and -4 precipitates (21,22), it has been suggested that FATPs are acyl-CoA ligases that directly couple LCFA uptake with CoA activation, thereby trapping fatty acids inside the cell.…”

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confidence: 99%

Targeted Deletion of Fatty Acid Transport Protein-4 Results in Early Embryonic Lethality

Gimeno

Hirsch

Punreddy

et al. 2003

Journal of Biological Chemistry

127

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Fatty acid transport protein-4 (FATP4) is the major FATP in the small intestine. We previously demonstrated, using in vitro antisense experiments, that FATP4 is required for fatty acid uptake into intestinal epithelial cells. To further examine the physiological role of FATP4, mice carrying a targeted deletion of FATP4 were generated. Deletion of one allele of FATP4 resulted in 48% reduction of FATP4 protein levels and a 40% reduction of fatty acid uptake by isolated enterocytes. However, loss of one FATP4 allele did not cause any detectable effects on fat absorption on either a normal or a high fat diet. Deletion of both FATP4 alleles resulted in embryonic lethality as crosses between heterozygous FATP4 parents resulted in no homozygous offspring; furthermore, no homozygous embryos were detected as early as day 9.5 of gestation. Early embryonic lethality has been observed with deletion of other genes involved in lipid absorption in the small intestine, namely microsomal triglyceride transfer protein and apolipoprotein B, and has been attributed to a requirement for fat absorption early in embryonic development across the visceral endoderm. In mice, the extraembryonic endoderm supplies nutrients to the embryo prior to development of a chorioallantoic placenta. In wild-type mice we found that FATP4 protein is highly expressed by the epithelial cells of the visceral endoderm and localized to the brush-border membrane of extraembryonic endodermal cells. This localization is consistent with a role for FATP4 in fat absorption in early embryogenesis and suggests a novel requirement for FATP4 function during development.

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Oligomerization of the Murine Fatty Acid Transport Protein 1

Cited by 36 publications

References 26 publications

Fatty acid transport protein 1 and long-chain acyl coenzyme A synthetase 1 interact in adipocytes

Fatty acid transport protein 1 and long-chain acyl coenzyme A synthetase 1 interact in adipocytes

Functional domains of the fatty acid transport proteins: Studies using protein chimeras

Targeted Deletion of Fatty Acid Transport Protein-4 Results in Early Embryonic Lethality

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