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

The CD36 (cluster of differentiation 36) antigen, a transmembrane glycoprotein, also called platelet glycoprotein IV (GPIV), and the PAS-4 protein (PASIV), have 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). Thus, it appears that CD36 takes up fatty acids, but it also binds to oxidized low-density lipoprotein in the liver and is involved in the development and progression of Nonalcoholic fatty liver disease (NAFLD) (Zhan et al. 2017).

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 co-receptor signaling is ligand specific. Cellular responses to these ligands are involved in angiogenesis, inflammatory responses, 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 expressed at reduced levels following leptin treatment. It acts as a fatty acid sink once fatty acids have crossed the plasma membrane. 

CD36 is reported to have diverse roles in lipid uptake, cell adhesion and pathogen sensing (see above). A Drosophila CD36 homologue, sensory neuron membrane protein 1 (SNMP1), has been shown to facilitate detection of lipid-derived pheromones by their cognate receptors in olfactory cilia. Gomez-Diaz et al. 2016 showed that 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.

Volatile compounds with an aldehyde moiety such as (Z)-9-octadecenal are potential ligands for CD36 that plays a role in mammalian olfaction. Straight-chain, saturated aliphatic aldehydes with 9-16 carbons exhibited CD36 ligand activities, albeit to varying degrees. Notably, the activities of tridecanal and tetradecanal were higher than that of oleic acid, the most potent ligand among the fatty acids tested. Among the aldehydes other than aliphatic aldehydes, only phenylacetaldehyde showed weak activity (Tsuzuki et al. 2017).

CD36 is a scavenger receptor class B protein (SR-B2), and it serves many functions in lipid metabolism and signaling. Glatz and Luiken 2018 reviewed CD36's role in facilitating cellular long-chain fatty-acid uptake across the plasma membrane, particularly in heart and skeletal muscle. CD36 acts in concert with other membrane proteins, such as peripheral plasma membrane fatty acid-binding protein (FABPpm), and is an intracellular docking site for cytoplasmic FABP (FABPc). The cellular fatty-acid uptake rate is governed primarily by the presence of CD36 at the cell surface, which is regulated by the subcellular vesicular recycling of CD36 from endosomes to the plasma membrane. CD36 has been implicated in dysregulated fatty acid and lipid metabolism in pathophysiological conditions, particularly in high-fat diet-induced insulin resistance and diabetic cardiomyopathy. It may be involved in signaling pathways and vesicular trafficking routes. Despite a poor understanding of its mechanism of action, CD36 has emerged as a pivotal membrane protein involved in whole-body lipid homeostasis (Glatz and Luiken 2018).

The reaction believed to be catalyzed or facilitated by CD36 is:

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

or

pheromone (out) → pheromone bound to a membrane receptor



This family belongs to the .

 

References:

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.

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.

Berkovic, S.F., L.M. Dibbens, A. Oshlack, J.D. Silver, M. Katerelos, D.F. Vears, R. Lüllmann-Rauch, J. Blanz, K.W. Zhang, J. Stankovich, R.M. Kalnins, J.P. Dowling, E. Andermann, F. Andermann, E. Faldini, R. D''Hooge, L. Vadlamudi, R.A. Macdonell, B.L. Hodgson, M.A. Bayly, J. Savige, J.C. Mulley, G.K. Smyth, D.A. Power, P. Saftig, and M. Bahlo. (2008). Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis. Am J Hum Genet 82: 673-684.

Cifarelli, V. and N.A. Abumrad. (2018). Intestinal CD36 and Other Key Proteins of Lipid Utilization: Role in Absorption and Gut Homeostasis. Compr Physiol 8: 493-507.

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.

Duttaroy, A.K. (2009). Transport of fatty acids across the human placenta: a review. Prog Lipid Res 48: 52-61.

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.

Glatz, J.F.C. and J.J.F.P. Luiken. (2018). Dynamic role of the transmembrane glycoprotein CD36 (SR-B2) in cellular fatty acid uptake and utilization. J Lipid Res. [Epub: Ahead of Print]

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.

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.

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.

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]

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.

Knipper, M., C. Claussen, L. Rüttiger, U. Zimmermann, R. Lüllmann-Rauch, E.L. Eskelinen, J. Schröder, M. Schwake, and P. Saftig. (2006). Deafness in LIMP2-deficient mice due to early loss of the potassium channel KCNQ1/KCNE1 in marginal cells of the stria vascularis. J. Physiol. 576: 73-86.

Lee, S., S. Tsuzuki, T. Amitsuka, D. Masuda, S. Yamashita, and K. Inoue. (2017). CD36 involvement in the olfactory perception of oleic aldehyde, an odour-active volatile compound, in mice. Biomed Res 38: 207-213.

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.

Luiken, J.J., D. Chanda, M. Nabben, D. Neumann, and J.F. Glatz. (2016). Post-translational modifications of CD36 (SR-B2): Implications for regulation of myocellular fatty acid uptake. Biochim. Biophys. Acta. 1862: 2253-2258.

Michelakakis, H., G. Xiromerisiou, E. Dardiotis, M. Bozi, D. Vassilatis, P.M. Kountra, G. Patramani, M. Moraitou, D. Papadimitriou, E. Stamboulis, L. Stefanis, E. Zintzaras, and G.M. Hadjigeorgiou. (2012). Evidence of an association between the scavenger receptor class B member 2 gene and Parkinson''s disease. Mov Disord 27: 400-405.

Orlowski, S., C. Coméra, F. Tercé, and X. Collet. (2007). Lipid rafts: dream or reality for cholesterol transporters? Eur Biophys. J. 36: 869-885.

Ou, M., R. Huang, Q. Luo, L. Xiong, K. Chen, and Y. Wang. (2019). Characterisation of scavenger receptor class B type 1 in rare minnow (Gobiocypris rarus). Fish Shellfish Immunol 89: 614-622.

Proudfoot, S.C. and D. Sahoo. (2019). Proline Residues in Scavenger Receptor-BI''s C-terminal Region Support Efficient Cholesterol Transport. Biochem. J. [Epub: Ahead of Print]

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.

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.

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.

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.

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.

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.

Tsuzuki, S., M. Yamasaki, Y. Kozai, T. Sugawara, Y. Manabe, K. Inoue, and T. Fushiki. (2017). Assessment of direct interaction between CD36 and an oxidized glycerophospholipid species. J Biochem 162: 163-172.

Tsuzuki, S., T. Amitsuka, T. Okahashi, Y. Kimoto, and K. Inoue. (2017). A Search for CD36 Ligands from Flavor Volatiles in Foods with an Aldehyde Moiety: Identification of Saturated Aliphatic Aldehydes with 9-16 Carbon Atoms as Potential Ligands of the Receptor. J Agric Food Chem 65: 6647-6655.

Wei, P., F.D. Sun, L.M. Zuo, J. Qu, P. Chen, L.D. Xu, and S.Z. Luo. (2017). Critical residues and motifs for homodimerization of the first transmembrane domain of the plasma membrane glycoprotein CD36. J. Biol. Chem. 292: 8683-8693.

Wingen, A., P. Carrera, O. Ekaterini Psathaki, A. Voelzmann, A. Paululat, and M. Hoch. (2017). Debris buster is a Drosophila scavenger receptor essential for airway physiology. Dev Biol. [Epub: Ahead of Print]

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.

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.

Zhan, Z., H. Ren, and M.L. Peng. (2017). [Role of CD36 in nonalcoholic fatty liver disease]. Zhonghua Gan Zang Bing Za Zhi 25: 953-956.

Zhang, W., R. Chen, T. Yang, N. Xu, J. Chen, Y. Gao, and R.A. Stetler. (2017). Fatty acid transporting proteins: Roles in brain development, aging, and stroke. Prostaglandins Leukot Essent Fatty Acids. [Epub: Ahead of Print]

Zhao, J., Z. Zhi, C. Wang, H. Xing, G. Song, X. Yu, Y. Zhu, X. Wang, X. Zhang, and Y. Di. (2017). Exogenous lipids promote the growth of breast cancer cells via CD36. Oncol Rep. [Epub: Ahead of Print]

Examples:

TC#NameOrganismal TypeExample
9.B.39.1.1

CD36 antigen; plasma membrane fatty acid transporter (Schwenk et al. 2010). Also called the scavenger receptor protein as it binds many ligands including both Gram-positive and Gram-negative bacteria; plays a role in immune development (Liu et al. 2016). Direct interaction of CD36 with glycerol phospholipids has been demonstrated (Tsuzuki et al. 2017). CD36 plays a role in the perception of specific odour-active volatile compounds including oleic aldehyde (cis-9-octadecenal), in the nasal cavity (Lee et al. 2017).

Animals and slime molds

CD36 of Mus musculus (Q08857)

 
9.B.39.1.2

Two component Carotenoid transporter CBP/Cameo2 (Sakudoh et al., 2010). Transports lutein, a carotenoid (Sakudoh et al. 2013). Since SCRB15 (9.B.39.1.5) transports β-carotene, CD30 family paralogues discriminate between different carotenoids (Sakudoh et al. 2013).

Soluble

Carotenoid transporter of Bombyx mori
Carotenoid-binding protein (CBP or yellow blood) (A4UVY6)
Membrane receptor and transporter, Cameo2 (D2KXB3)

 
9.B.39.1.3

Scavenger receptor class B, member 1 (SR-B1; SCARB1; CD3621; CLA1) of 552 aas and 2 TMSs. It comprises the hepatits C receptor together with its co-receptor, CD81 tetraspanin (Bartosch et al., 2003). When defective, it leads to antibody deficiency. SR-B1 is a receptor for different ligands such as phospholipids, cholesterol esters, lipoproteins, phosphatidylserine and apoptotic cells (Proudfoot and Sahoo 2019). It facilitates the flux of free and esterified cholesterol between the cell surface and extracellular donors and acceptors, such as high density lipoproteins (HDL) and to a lesser extent, apoB-containing lipoproteins and modified lipoproteins (Orlowski et al. 2007). It is necessary for selective HDL-cholesterol uptake (Zanoni et al. 2016). Probably involved in the phagocytosis of apoptotic cells, via its phosphatidylserine binding activity.  Several proteins have been implicated in fatty acid transport by enterocytes including the scavenger receptor CD36 (SR-B2), the scavenger receptor B1 (SR-B1), and the FA transport protein 4 (FATP4) (Cifarelli and Abumrad 2018).

Animals

SR-B1 of Homo sapiens (Q8WTV0)

 
9.B.39.1.4

Putative fatty acid translocase, CD36 glycoprotein (FA translocase; FAT/CD36/SR-B2) (Glatz and Luiken 2017; Zhang et al. 2017).  It is a Leukocyte differentiation antigen and adhesin of 472 aas protein with 2 TMSs, one N-terminal and one C-terminal (Schwenk et al. 2010). Studies have shown that TMS 1 plays a role in formation of a homodimeric structure which may be involved in regulating signal transduction (Wei et al. 2017). Uptake of long chain unsaturated fatty acids, eicosapentaenoic acid and docosahexaenoic acid, is facilitated by CD36/SR-B2 (Glatz and Luiken 2017). Glycosylation, ubiquitination and palmitoylation are involved in regulating CD36 stability, while phosphorylation at extracellular sites affect the rate of fatty acid uptake (Luiken et al. 2016). CD36 may facilitate fatty acid uptake by an indirect mechanism (Jay and Hamilton 2016), but fatty acid uptake studies in breast cancer cells is consistent with its role in transport (Zhao et al. 2017).

Animals

CD36 of Homo sapiens (P16671)

 
9.B.39.1.5

Scavenger receptor class B member 1 protein 15, SCRB15 of 504 aas and 2 TMSs.  Transports β-carotene to the silk gland. Encoded by the Flesh (F) gene. 26% identical to the yellow cocoon gene product Cameo2, the lutein transporter (9.B.39.1.2; Sakudoh et al. 2013). 

Insects

SCRB15 of Bombyx mori (K7ZLU1)

 
9.B.39.1.6

Sensory neuron membrane protein 1, SNMP1 of 551 aas and 2 TMSs (N- and C-terminal). Plays an olfactory role that is not restricted to pheromone sensitivity. Has a role in detection and signal transduction of the fatty-acid-derived male pheromone 11-cis vaccenyl acetate (cVA). Not required for sensitivity to general odorants. Acts in concert with Or67d and lush to capture cVA molecules on the surface of Or67d expressing olfactory dendrites and facilitate their transfer to the odorant-receptor Orco complex. Essential for the electrophysiological responses of these olfactory sensory neurons (Benton et al. 2007; Jin et al. 2008; Gomez-Diaz et al. 2016).

SNMP1 of Drosophila melanogaster (Fruit fly)

 
9.B.39.1.7

Croquemort isoform 1 (CD36) of 259 aas and 2 TMSs, a homologue of human CD36, is a member of class B scavenger receptors, which are involved in phagocytosis of bacteria and cytokine release. Croquemort from Pacific white shrimp  (LvCroquemort) and its truncated form (LvCroquemort-S1) cDNA sequences have been identified (Hou et al. 2017). LvCroquemort transcripts are highly expressed in gills, hemocytes and testis.  Knock-down of LvCroquemort reduces bacterial clearance (Hou et al. 2017).

Croquemort isoform 1 (CD36) of Litopenaeus vannamei

 
9.B.39.1.8

Debris buster, Dsb of 615 aas and 2 TMSs, one near the N-terminus, and one near the C-terminus. Drosophila has 14 SR-B members whose functions are not well known. It is one of the scavenger receptors class B (SR-B) which are multifunctional transmembrane proteins which in vertebrates participate in lipid transport, pathogen clearance, lysosomal delivery and intracellular sorting. Dsb sorts components of the apical extracellular matrix which are essential for airway physiology. Since SR-B LIMP2-deficient mice show reduced expression of several apical plasma membrane proteins, sorting of proteins to the apical membrane is likely an evolutionary conserved function of Dsb and LIMP2 (Wingen et al. 2017).

The debris buster of Drosophila melanogaster

 
9.B.39.1.9

Lysosomal membrane protein 2, LIMP2 or Scarb2, of 478 aas and 2 TMSs, N- and C-terminal.  LIMP2 plays a role in the regulation of membrane transport processes in the endocytic pathway. Knipper et al. 2006 showed that LIMP2-deficient mice display a progressive high-frequency hearing loss and decreased otoacoustic emissions as early as 4 weeks of age. The decline of functional KCNQ1/KCNE1 is likely to be the primary cause of the hearing loss because LIMP2 controls the localization and the level of apically expressed membrane proteins such as KCNQ1, KCNE1 in the stria vascularis (Knipper et al. 2006). LIMP2 deficiency also causes myoclonus epilepsy and glomerulosclerosis (Berkovic et al. 2008) and genetic variants are associated with Gaucher and Parkinson's diseases (Michelakakis et al. 2012). The pathologies associated with LIMP2 have been reviewed (Dibbens et al. 2016; Zigdon et al. 2017).

LIMP2 of Mus musculus (Mouse)

 
Examples:

TC#NameOrganismal TypeExample
9.B.39.10

Lysosome membrane protein II or scavenger receptor class B type 2a, Scarb2a, of 531 aas and 2 TMSs, N- and C-terminal. In the rare minnow, Gobiocypris rarus, it is the grass carp reovirus receptor, GCRV (Ou et al. 2019).