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9.B.39 The Long Chain Fatty Acid Translocase (lcFAT) Family

The CD36 antigen, also called platelet glycoprotein IV (GPIV) and the PAS-4 protein (PASIV), has been implicated in the uptake of long chain fatty acids in mouse tissues such as heart, skeletal muscle and adipose tissue (Coburn et al., 2000). The mouse protein, of 472 aas, exhibits two hydrophobic segments that may be TMSs, one at its extreme N-terminus, and one at its extreme C-terminus. Xu et al. 2013 concluded that CD36 enhances fatty acid uptake by increasing the rate of intracellular esterification rather than transport.  However, others have concluded that CD36 homologues do function in transport (Duttaroy 2009; Harasim et al. 2008). 

CD36 is a multifunctional glycoprotein that acts as a receptor for a broad range of ligands. Ligands can be of a proteinaceous nature like thrombospondin, fibronectin, collagen or amyloid-beta as well as of lipidic nature such as oxidized low-density lipoprotein (oxLDL), anionic phospholipids, long-chain fatty acids and bacterial diacylated lipopeptides. They are generally multivalent and can therefore engage multiple receptors simultaneously with the formation of CD36 clusters which initiate signal transduction and internalization of receptor-ligand complexes. The dependency on coreceptor signaling is strongly ligand specific. Cellular responses to these ligands are involved in angiogenesis, inflammatory response, fatty acid metabolism, taste and dietary fat processing in the intestine. CD36 binds long-chain fatty acids and facilitates their transport into cells, thus participating in muscle lipid utilization, adipose energy storage, and gut fat absorption (see above) (Smith et al. 2008; Tran et al. 2011).

Leptin has been shown to increase fatty acid oxidation and intramuscular triacylglycerol hydrolysis. Chronic leptin administration decreases fatty acid uptake and reduces mRNA levels of FAT/CD36 in rat skeletal muscle (Steinberg et al., 2002). The plasma membrane-associated fatty acid binding protein (FABPpm), also implicated in fatty acid transport, was also expressed at reduced levels following leptin treatment. It acts as a fatty acid sink once fatty acids have crossed the plasma membrane. 

CD36 transmembrane proteins are reported to have diverse roles in lipid uptake, cell adhesion and pathogen sensing (see above), but it is not known how they function. A Drosophila CD36 homologue, sensory neuron membrane protein 1 (SNMP1), had previously been shown to facilitate detection of lipid-derived pheromones by their cognate receptors in olfactory cilia. Gomez-Diaz et al. 2016 investigated how SNMP1 functions in vivo. SNMP1's ectodomain is essential, but intracellular and transmembrane domains are dispensable, for cilia localization and pheromone-evoked responses. SNMP1 can be substituted by mammalian CD36, whose ectodomain can interact with insect pheromones. Homology modelling, using the mammalian LIMP-2 structure as template, revealed a putative tunnel in the SNMP1 ectodomain that is sufficiently large to accommodate pheromone molecules. Amino-acid substitutions predicted to block this tunnel diminished pheromone sensitivity. Gomez-Diaz et al. 2016 proposed a model in which SNMP1 funnels hydrophobic pheromones from the extracellular fluid to integral membrane receptors.

The reaction believed to be catalyzed by CD36 is:

long chain fatty acid (out) → long chain fatty acid (in)

or

pheromone (out) → pheromone bound to a membrane receptor

References associated with 9.B.39 family:

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Benton, R., K.S. Vannice, and L.B. Vosshall. (2007). An essential role for a CD36-related receptor in pheromone detection in Drosophila. Nature 450: 289-293. 17943085
Coburn, C.T., F.F. Knapp, Jr., M. Febraio, A.L. Beets, R.L. Silverstein and N. Abumrad (2000). Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice. J. Biol. Chem. 275: 32523-32529. 10913136
Duttaroy, A.K. (2009). Transport of fatty acids across the human placenta: a review. Prog Lipid Res 48: 52-61. 19041341
Glatz, J.F. and J.J. Luiken. (2017). From fat to FAT (CD36/SR-B2): Understanding the regulation of cellular fatty acid uptake. Biochimie 136: 21-26. 28013071
Gomez-Diaz, C., B. Bargeton, L. Abuin, N. Bukar, J.H. Reina, T. Bartoi, M. Graf, H. Ong, M.H. Ulbrich, J.F. Masson, and R. Benton. (2016). A CD36 ectodomain mediates insect pheromone detection via a putative tunnelling mechanism. Nat Commun 7: 11866. 27302750
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Hou, F., T. Liu, Q. Wang, Y. Liu, C. Sun, and X. Liu. (2017). Identification and characterization of two Croquemort homologues in penaeid shrimp Litopenaeus vannamei. Fish Shellfish Immunol 60: 1-5. 27670083
Jay, A.G. and J.A. Hamilton. (2016). The enigmatic membrane fatty acid transporter CD36: New insights into fatty acid binding and their effects on uptake of oxidized LDL. Prostaglandins Leukot Essent Fatty Acids. [Epub: Ahead of Print] 27288302
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Orlowski, S., C. Coméra, F. Tercé, and X. Collet. (2007). Lipid rafts: dream or reality for cholesterol transporters? Eur Biophys. J. 36: 869-885. 17576551
Sakudoh, T., S. Kuwazaki, T. Iizuka, J. Narukawa, K. Yamamoto, K. Uchino, H. Sezutsu, Y. Banno, and K. Tsuchida. (2013). CD36 homolog divergence is responsible for the selectivity of carotenoid species migration to the silk gland of the silkworm Bombyx mori. J Lipid Res 54: 482-495. 23160179
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Schwenk, R.W., G.P. Holloway, J.J. Luiken, A. Bonen, and J.F. Glatz. (2010). Fatty acid transport across the cell membrane: regulation by fatty acid transporters. Prostaglandins Leukot Essent Fatty Acids 82: 149-154. 20206486
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Steinberg, G.R., D.J. Dyck, J. Calles-Escandon, N.N. Tandon, J.J.F.P. Luiken, J.F.C. Glatz, and A. Bonen. (2002). Chronic leptin administration decreases fatty acid uptake and fatty acid transporters in rat skeletal muscle. J. Biol. Chem. 277: 8854-8860. 11729182
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