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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)


pheromone (out) → pheromone bound to a membrane receptor.



References associated with 9.B.39 family:

Bartosch, B., A. Vitelli, C. Granier, C. Goujon, J. Dubuisson, S. Pascale, E. Scarselli, R. Cortese, A. Nicosia, and F.L. Cosset. (2003). Cell entry of hepatitis C virus requires a set of co-receptors that include the CD81 tetraspanin and the SR-B1 scavenger receptor. J. Biol. Chem. 278: 41624-41630. 12913001
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
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
Harasim, E., A. Kalinowska, A. Chabowski, and T. Stepek. (2008). [The role of fatty-acid transport proteins (FAT/CD36, FABPpm, FATP) in lipid metabolism in skeletal muscles]. Postepy Hig Med Dosw (Online) 62: 433-441. 18772848
Jin, X., T.S. Ha, and D.P. Smith. (2008). SNMP is a signaling component required for pheromone sensitivity in Drosophila. Proc. Natl. Acad. Sci. USA 105: 10996-11001. 18653762
Liu, K., Y. Xu, Y. Wang, S. Wei, D. Feng, Q. Huang, S. Zhang, and Z. Liu. (2016). Developmental expression and immune role of the class B scavenger receptor cd36 in zebrafish. Dev Comp Immunol 60: 91-95. 26915754
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
Sakudoh, T., T. Iizuka, J. Narukawa, H. Sezutsu, I. Kobayashi, S. Kuwazaki, Y. Banno, A. Kitamura, H. Sugiyama, N. Takada, H. Fujimoto, K. Kadono-Okuda, K. Mita, T. Tamura, K. Yamamoto, and K. Tsuchida. (2010). A CD36-related transmembrane protein is coordinated with an intracellular lipid-binding protein in selective carotenoid transport for cocoon coloration. J. Biol. Chem. 285: 7739-7751. 20053988
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
Smith, J., X. Su, R. El-Maghrabi, P.D. Stahl, and N.A. Abumrad. (2008). Opposite regulation of CD36 ubiquitination by fatty acids and insulin: effects on fatty acid uptake. J. Biol. Chem. 283: 13578-13585. 18353783
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
Tran, T.T., H. Poirier, L. Clément, F. Nassir, M.M. Pelsers, V. Petit, P. Degrace, M.C. Monnot, J.F. Glatz, N.A. Abumrad, P. Besnard, and I. Niot. (2011). Luminal lipid regulates CD36 levels and downstream signaling to stimulate chylomicron synthesis. J. Biol. Chem. 286: 25201-25210. 21610069
Xu, S., A. Jay, K. Brunaldi, N. Huang, and J.A. Hamilton. (2013). CD36 Enhances Fatty Acid Uptake by Increasing the Rate of Intracellular Esterification but Not Transport across the Plasma Membrane. Biochemistry 52: 7254-7261. 24090054
Zanoni, P., S.A. Khetarpal, D.B. Larach, W.F. Hancock-Cerutti, J.S. Millar, M. Cuchel, S. DerOhannessian, A. Kontush, P. Surendran, D. Saleheen, S. Trompet, J.W. Jukema, A. De Craen, P. Deloukas, N. Sattar, I. Ford, C. Packard, A.a. Majumder, D.S. Alam, E. Di Angelantonio, G. Abecasis, R. Chowdhury, J. Erdmann, B.G. Nordestgaard, S.F. Nielsen, A. Tybjærg-Hansen, R.F. Schmidt, K. Kuulasmaa, D.J. Liu, M. Perola, S. Blankenberg, V. Salomaa, S. Männistö, P. Amouyel, D. Arveiler, J. Ferrieres, M. Müller-Nurasyid, M. Ferrario, F. Kee, C.J. Willer, N. Samani, H. Schunkert, A.S. Butterworth, J.M. Howson, G.M. Peloso, N.O. Stitziel, J. Danesh, S. Kathiresan, D.J. Rader, , , and. (2016). Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science 351: 1166-1171. 26965621