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 (LCFAs) 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 homologues always have 2 TMSs, one N-terminal and one C-terminal, but other potential TMSs of moderate hydrophobicities are present between these two. While some investigators have concluded that CD36 is a fatty acid transporter, others question this suggestion (Wade et al. 2021). CD36 mediates intestinal absorption of dietary astaxanthin and affects its secretion (Liu et al. 2023).

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). Jay et al. 2020 have concluded that LCFAs diffuse rapidly across biological membranes and do not require an active protein transporter such as CD36 for their transmembrane movement.

Vitamins D, E, and K as well as carotenoids are not absorbed solely through passive diffusion (Reboul 2022). Broad-specificity membrane transporters such as SR-BI (scavenger receptor class B type I; TC# 9.B.39.1.3), CD36 (TC# 9.B.39.1.1), NPC1L1 (Niemann Pick C1-like 1; TC# 1.A.6.6.6) or ABCA1 (ATP-binding cassette A1; TC# 3.A.1.211.14) are involved in the uptake of these micronutrients from the lumen to the enterocyte cytosol and in their secretion into the bloodstream. The existence of efflux pathways from the enterocyte back to the lumen or from the bloodstream to the lumen, involving ABCB1 (P-glycoprotein/MDR1; TC# 3.A.1.201.1) or the ABCG5/ABCG8 complex (TC# 3.A.1.204.5), have also been evidenced for vitamins D and K. Surprisingly, no membrane proteins have yet been involved in dietary vitamin A uptake. After an overview of the metabolism of fat-soluble vitamins and carotenoids along the gastrointestinal tract (from the mouth to the colon where interactions with microbiota may occur), a focus is placed on the identified and candidate proteins participating in the apical uptake, intracellular transport, basolateral secretion and efflux back to the lumen of fat-soluble vitamins and carotenoids in enterocytes (Reboul 2022). This review also highlights the mechanisms that remain to be identified to fully unravel the pathways involved in fat-soluble vitamin and carotenoid intestinal absorption.

Cluster of differentiation 36 (CD36) belongs to the B2 receptors of the scavenger receptor class B family, which is comprised of single-chain secondary transmembrane glycoproteins (Yang et al. 2022). It is present in a variety of cell types, including monocytes, macrophages, microvascular endothelial cells, adipocytes, hepatocytes, platelets, skeletal muscle cells, kidney cells, cardiomyocytes, taste bud cells, and a variety of other cell types. CD36 can be localized to the cell surface, mitochondria, endoplasmic reticulum, and endosomes, playing roles in lipid accumulation, oxidative stress injury, apoptosis, and inflammatory signaling. It is expressed in a variety of ocular cells, including retinal pigment epithelia (RPE), retinal microvascular endothelial cells, retinal ganglion cells (RGC), Muller cells, and photoreceptor cells, playing important roles in eye diseases, such as age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma. A comprehensive understanding of CD36 function and downstream signaling pathways is for the prevention and treatment of eye diseases. Yang et al. 2022 reviewed the molecular characteristics, distribution, and function of scavenger receptor CD36 and its role in ophthalmology.

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

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


pheromone (out) → pheromone bound to a membrane receptor



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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.

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TC#NameOrganismal TypeExample

CD36 (cluster of differentiation 36) antigen; once thought to be a plasma membrane fatty acid transporter of 472 aas and 2 TMSs, N- and C-terminal (Schwenk et al. 2010). Also called the scavenger receptor protein (SR-B2) as it binds many ligands including both Gram-positive and Gram-negative bacteria; it 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). Jay et al. 2020 have concluded that LCFAs diffuse rapidly across biological membranes and do not require an active protein transporter such as CD36 for their transmembrane movement. CD36 (SR-B2) may be a target to treat lipid overload-induced  cardiac dysfunction (Glatz et al. 2020). CD36 is released into the circulation (cCD36) of WT mice in response to tail-vein injection of oxPCCD36. The presence of cCD36 in hyperlipidemia revealed  a link between cCD36 and oxidized phospholipids generated under oxidative stress and low-grade inflammation associated with hyperlipidemia (Biswas et al. 2021). Inhibition of fatty acid translocase (FAT/CD36) palmitoylation enhances hepatic fatty acid beta-oxidation by increasing its localization to mitochondria and interaction with long-chain acyl-CoA synthetase 1 (Zeng et al. 2022). CD36 expression is related to human epidermal growth factor receptor 2 (HER2)-positive breast cancer (Ligorio et al. 2022).  A CD36 transmembrane domain peptide interrupts CD36 interactions with membrane partners on macrophages and inhibits atherogenic functions (Huang et al. 2023). CD36 is a transmembrane glycoprotein receptor for oxidized low density lipoprotein (LDL) and other endogenous danger signals and promotes athero-thrombotic processes. CD36 associates physically with other transmembrane proteins, including integrins, tetraspanins, and toll-like receptors, which modulate CD36-mediated cell signaling. The CD36 N-terminal TMS contains a GXXXG sequence motif that mediates protein-protein interactions with many membrane proteins. Huang et al. 2023 thus hypothesized that the nTMS is involved in CD36 interactions with other membrane proteins. CD36 interactions with partner cell surface proteins on murine peritoneal macrophages were detected with an immunofluorescence-based proximity ligation cross linking assay (PLA) and confirmed by immunoprecipitation/immunoblot. Prior to performing these assays, cells were incubated with a synthetic 29 amino acid peptide containing the 22 amino acids of CD36 nTMD or a control peptide in which the glycine residues in GXXXG motif were replaced by valines. Macrophages were preincubated with peptides and then treated with oxLDL to assess LDL uptake and other properties. CD36 nTMD peptide treated cells compared to untreated or control peptide treated cells showed decreased CD36 surface associations with tetraspanin CD9 (TC# 8.A.40.1.9) and ameliorated pathologically important CD36 mediated responses to oxLDL, including uptake of DiI-labeled oxLDL, foam cell formation, ROS generation, and inhibition of migration (Huang et al. 2023). CD36 may play a role in transmembrane transport and tissue partition of per- and polyfluoroalkyl substances (PFASs) in mice (Jia et al. 2023).


Animals and slime molds

CD36 of Mus musculus (Q08857)


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).

Scarb2a of Danio rerio


Sensory neuron membrane protein 1, SNMP1, of 523 aas and 2 TMSs, N- and C-terminal, and possibly one more TMS internally. The expression patterns of SNMP1 and SNMP2 have been determined, indicating distinct functions for these two CD36-related proteins in the olfactory system (Blankenburg et al. 2019).

SNMP1 of Heliothis virescens (Tobacco budworm moth)


Sensory neuron membrane protein 2, SNMP2, of 520 aas and 2 TMSs, N- and C-terminal, and possibly one more TMS internally. The expression patterns of SNMP1 and SNMP2 have been determined, and they differ greatly, indicating distinct functions for these two CD36-related proteins in the olfactory system (Blankenburg et al. 2019).

ANMP2 of Heliothis virescens (Tobacco budworm moth)


Lysosomal integral membrane homodimeric protein 2, LIMP2. SCARB2, CD36L2, or LIMPII, of 478 aas and two TMSs at the N- and C-termini. It acts as a lysosomal receptor for glucosylceramidase (GBA) targeting (Reczek et al. 2007) as well as a receptor for enterovirus 71 (Yamayoshi et al. 2009; Zhou et al. 2019). It plays a role in the activation of autophagy (Sakane et al. 2020). It may also function in aminophospholipid transport.

LIMP2 or SCARB2 of Homo sapiens


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).


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


Scavenger receptor class B, member 1 (SR-B1; SCARB1; CD36L1; CLA1) of 552 aas and 2 very hydrophobic TMSs, one at the N-terminus and one near the C-terminus, possibly with as many as 3 other less hydrophobic 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). It is 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). Fatty acetates are volatile compounds that bind specifically to amino acid region 149-168 of CD36 (Tsuzuki et al. 2022). SR-BI is highly expressed in liver and steroidogenic tissues (Yu 2022). It regulates selective uptake of cholesterol esters (CEs) from HDL, revealing its role in mediating reverse cholesterol transport (RCT) and steroid hormone synthesis. In addition, SR-BI is involved in cholesterol transport, cellular inflammatory responses, platelet reactivity, and HDL-initiated signaling in the vascular system in several mouse models. Mutations in the human SR-BI gene (SCARB1) have been found to be associated with abnormally high plasma HDL-C levels and an increased risk of atherosclerotic cardiovascular disease. The key regions of SR-BI transmembrane structure and the regulatory mechanisms of SR-BI expression have been reviewed (Yu 2022). A short amphipathic alpha helix in scavenger receptor BI facilitates bidirectional HDL-cholesterol transport through a hydrophobic tunnel within SR-BI (May and Sahoo 2022).  A deficiency of SR-B1 reduced the tumor load of colitis-induced or APCmin /+ -induced colorectal cancer (Chen et al. 2023).


SR-B1 of Homo sapiens (Q8WTV0)


Putative fatty acid translocase, CD36 glycoprotein (FA translocase; FAT/CD36/SR-B2; Collagen type I receptor; thrombospondin receptor) (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 affects 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 are consistent with its role in transport (Zhao et al. 2017). CD36 is also a co-receptor that enhances the response to MICs of Toxoplasma gondii (Costa Mendonça-Natividade et al. 2019). CD36 is expressed in multiple cell types, mediates lipid uptake, immunological recognition, inflammation, molecular adhesion, and apoptosis. CD36 is a transmembrane glycoprotein that contains several posttranslational modification sites and binds to diverse ligands, including apoptotic cells, thrombospondin-1 (TSP-1), and fatty acids (FAs) (Wang and Li 2019). CD36 is responsible for several metabolic disorders. It is a multifunctional scavenger receptor mediating uptake of long-chain fatty acids. Akachar et al. 2021 determined whether Lys164, exposed to the protein surface, played roles in fatty acid uptake. Conformational changes involved Lys164 which influenced the folding, utility, solubility, and stability of the protein. It also provided the structural basis for forming an opening near the principal portal for the dissociation of palmitic acid (Akachar et al. 2021). How CD36 regulates the tumor microenvironment has been reviewed (Liao et al. 2022). CD36 mediates SARS-CoV-2-envelope-protein-induced platelet activation and thrombosis by direct binding (Tang et al. 2023). It is a skeletal muscle protein, involved in fatty acid transport, that influences fatty acid oxidation rates (Maunder et al. 2023).

observed during exercise.


CD36 of Homo sapiens (P16671)


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). 


SCRB15 of Bombyx mori (K7ZLU1)


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)


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


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 evolutionarily conserved function of Dsb and LIMP2 (Wingen et al. 2017).

The debris buster of Drosophila melanogaster


Lysosomal membrane protein 2, LIMP2, LIMP-2, LIMPII, LGP85 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).  LIMP-2 is ubiquitinated in the N-terminal cytoplasmic domain (Fujimoto et al. 2020). It is involved in the activation of autophagy (Sakane et al. 2020).

LIMP2 of Mus musculus (Mouse)


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