PET imaging of FABPs

Fatty acid binding proteins (FABPs) are small (14-15 kDa) cytosolic proteins that bind unesterified long-chain fatty acids (LCFAs) and eicosanoids, and some other hydrophobic ligands, with nanomolar affinity. FABPs participate in fatty acid (FA) transport, metabolism, and lipid storage, and play a role in inflammatory responses. FABPs bind cannabinoids and endocannabinoids, transporting them to intracellular catabolic enzymes. In addition to FABPs, myoglobin binds fatty acids, which may have role in regulation of FA and oxygen metabolism in cardiomyocytes and type 1 myocytes.

Humans have at least 8 FABP isoforms:

Liver contains FABP1, which transports LCFAs to mitochondria for β-oxidation, and interacts with PPARα nuclear receptors.

Intestine contains FABP1 and FABP2, and the distal small intestine contains also FABP6. FABP1 participates in transport of LCFAs into β-oxidation, incorporation of monoglycerides into phospholipids, and production of chylomicrons. FABP2 directs LCFAs into triglyceride synthesis. FABP6 transports bile acids.

Cardiac and skeletal muscle contains FABP3, which transports LCFAs to β-oxidation and phospholipid and triglyceride synthesis, and interacts with nuclear receptors. Endothelial cells in these tissues contain FABP4 and FABP5, of which at least FABP4 is regulated by VEGF.

Adipose tissue has very high levels of FABP4, and very low levels of FABP5. FABPs play a role in triglyceride (TG) storage, regulation of FA concentrations, production of inflammatory cytokines, and interact with PPAR nuclear receptors.

Macrophages contain FABP4 and FABP5, functioning in cytokine production, and interacting with PPARγ nuclear receptors and JAK2 signaling pathway.

Central nervous system contains FABP3, FABP5, and FABP7. FABP3 supplies arachidonic acid for production of phospholipids, and maintains balance between certain polyunsaturated FAs. FABP5 supplies LCFAs for production of membranes, participates in retinoic acid utilization, and interacts with nuclear receptors. FABP7 provides neurons with docosahexaenoic acid for membrane synthesis and signalling. In peripheral nervous system, FABP8 (not found in the brain) participates in production of lipids for the myelin membranes.

In addition to its intracellular functions, FABP4 is also an adipokine, secreted from adipocytes and macrophages. FABP4 is therefore assumed to mediate the inflammatory responses linked to lipid metabolism, and have a role in metabolic syndrome and atherosclerosis. Vascular inflammation, measured using [18F]FDG PET, is independently associated with FABP4 concentration in plasma (Yoo et al., 2011).

Effects of FABPs on FA uptake have been studied with labeled fatty acid ligands, such as [125I]BMIPP, in mice strains which do not express certain FABP subtypes.

A PET tracer for FABP4, [18F]FTAP1 has been developed and validated in mouse tumour model (Temma et al., 2015).

FABPpm

Plasma membrane fatty acid binding protein (FABPpm) is a protein located at plasma membrane in several tissues, at least in the liver, heart and skeletal muscle, adipose tissue, and intestine. It is also located in the mitochondria where it has the name mitochondrial aspartate aminotransferase (mAspAt). It transports long-chain fatty acids across the plasma membrane, together with fatty acid transport proteins and fatty acid translocase/CD36.


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References:

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Elmes MW, Kaczocha M, Berger WT, Leung K, Ralph BP, Wang L, Sweeney JM, Miyauchi JT, Tsirka SE, Ojima I, Deutsch DG. Fatty acid-binding proteins (FABPs) are intracellular carriers for Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). J Biol Chem. 2015; 290(14): 8711-8721.

Furuhashi M, Saitoh S, Shimamoto K, Miura T. Fatty Acid-Binding Protein 4 (FABP4): Pathophysiological Insights and Potent Clinical Biomarker of Metabolic and Cardiovascular Diseases. Clin Med Insights Cardiol. 2015; 8(Suppl 3): 23-33.

Hotamisligil GS, Bernlohr DA. Metabolic functions of FABPs - mechanisms and therapeutic implications. Nat Rev Endocrinol. 2015; 11: 592-605.

Iso T, Maeda K, Hanaoka H, Suga T, Goto K, Syamsunarno MR, Hishiki T, Nagahata Y, Matsui H, Arai M, Yamaguchi A, Abumrad NA, Sano M, Suematsu M, Endo K, Hotamisligil GS, Kurabayashi M. Capillary endothelial fatty acid binding proteins 4 and 5 play a critical role in fatty acid uptake in heart and skeletal muscle. Arterioscler Thromb Vasc Biol. 2013; 33(11): 2549-2557.

Smathers RL, Petersen DR. The human fatty acid-binding protein family: evolutionary divergencies and functions. Hum Genomics 2011; 5(3): 170-191.

Storch J, Thumser AE. Tissue-specific functions in the fatty acid-binding protein family. J Biol Chem. 2010; 285(43): 32679-32683.

Temma T, Nishigori K, Onoe S, Sampei S, Kimura I, Ono M, Saji H. Radiofluorinated probe for PET imaging of fatty acid binding protein 4 in cancer. Nucl Med Biol. 2015; 42: 184-191.

Thumser AE, Moore JB, Plant NJ. Fatty acid binding proteins: tissue-specific functions in health and disease. Curr Opin Clin Nutr Metab Care 2014; 17(2): 124-129.

Yoo HJ, Kim S, Park MS, Choi HY, Yang SJ, Seo JA, Kim SG, Kim NH, Baik SH, Choi DS, Choi KM. Serum adipocyte fatty acid-binding protein is associated independently with vascular inflammation: analysis with 18F-fluorodeoxyglucose positron emission tomography. J Clin Endocrinol Metab. 2011; 96(3): E488-E492.



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Created at: 2015-10-13
Updated at: 2018-12-09
Written by: Vesa Oikonen