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 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.
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