CD36 Enhances Fatty Acid Uptake by Increasing the Rate of Intracellular Esterification but Not Transport across the Plasma Membrane

Abstract

CD36 is a multifunctional protein that enhances cellular fatty acid (FA) uptake, a key step in energy metabolism, and its dysregulation in multiple tissue sites is central to obesity-linked diabetes, a risk factor for atherosclerosis. Although CD36 has been implicated in FA uptake in a correlative way, the molecular mechanisms are not known. Their elucidation in cells is confounded by receptor-mediated uptake of low-density lipoprotein by CD36 and the competitive and/or contributive effects of other proteins involved in FA transport and metabolism, which include caveolin(s), fatty acid transport protein (FATP), intracellular fatty acid binding protein, and enzymes involved in the conversion of FAs to esters. Here we utilized a simpler cellular system (HEK cells), which lack caveolin-1, CD36, and FATP and metabolize FAs slowly compared to the time frame of transmembrane FA movement. Our previous studies of HEK cells showed that caveolin-1 affects FA binding and translocation across the plasma membrane and but not FA esterification [Simard, J. R., et al. (2010) J. Lipid Res. 51 (5), 914-922]. Our key new finding is that CD36 accelerates FA uptake and extensive incorporation into triglycerides, a process that is slower (minutes) than transmembrane movement (seconds). Real-time fluorescence measurements showed that the rates of binding and transport of oleic acid into cells with and without CD36 were not different. Thus, CD36 enhances intracellular metabolism, i.e., esterification, and thereby increases the rate of FA uptake without catalyzing the translocation of FA across the plasma membrane, suggesting that CD36 is central to FA uptake via its effects on intracellular metabolism.

Structure-Function of CD36 and Importance of Fatty Acid Signal Transduction in Fat Metabolism

“…Mice deficient in caveolin-1 are lean and protected from high fat diet induced adiposity (75). Although caveolins might influence FA uptake by modulating CD36 localization to lipid rafts, CD36-independent effects of caveolin on FA uptake can be observed (17, 99). In the intestine caveolin-1 is expressed on enterocyte brush border membranes and the apically absorbed FA appears to be internalized by enterocytes in detergent resistant and caveolin-1 containing vesicles that also contain alkaline phosphatase and CD36.…”

Overexpression of full-length cholesteryl ester transfer protein in SW872 cells reduces lipid accumulation

“…CD36 is a plasma membrane receptor that binds multiple ligands including fatty acids ( 30,39 ). Recent studies have suggested that CD36 does not directly transport fatty acids across the plasma membrane, but rather through signaling events or direct interaction with enzymes such as acyl-CoA synthetase it enhances fatty acid uptake and promotes TG synthesis ( 40 ). CD36 mRNA levels were reduced by 90% in CETP + cells grown in oleatecontaining media, suggesting that reduced fatty acid uptake may explain the reduced fl ux of fatty acids through the TG biosynthetic pathway.…”

Molecular mechanisms of fatty liver in obesity

“…However, in the insulin-resistant state, which is a condition often associated with central obesity, adipocyte lipolysis increases regardless of nutritional fluctuations, leading to the release of abundant FFAs into the blood [12]. In the liver, several membrane-bound proteins are responsible for transporting circulating FFAs into hepatocytes, including fatty acid transporter protein (FATP)-2 [15], FATP-5 [16], fatty acid translocase (FAT/CD36) [17][18][19], caveolins [20,21], fatty acid binding proteins (FABP)-1, FABP-4, and FABP-5 [22,23]. Upregulation of several FFA transporters is associated with increased insulin resistance and hepatic steatosis in NAFLD patients [24][25][26][27].…”