Obesity, along with diabetes and associated consequences like cardiovascular, neurological and renal diseases, is increasing worldwide. Along with focusing on smarting eating, research is on to understand the biological mechanisms.

In obesity, fatty acids, derived mostly from adipose tissue, alter lipid metabolism in other tissues such as liver and skeletal muscles. Both impaired fatty acid metabolism and glucose are hallmarks of diabetes.

In a recent study in the journal Biochemistry, a research group applied fluorescent methods to measure the rate by which fatty acids bind to and move across the fatty acid membrane to become metabolized.  

Previous research has shown that glucose transport under the control of insulin is mediated by a transport protein called GLUT4. However, how fatty acids enter into cells has been an important unsolved problem, especially whether there are gatekeeper plasma membrane proteins that regulate fatty acid translocation across the membrane, thereby controlling the supply of fatty acids to the interior of the cell.

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. Credit and link: 
DOI: 10.1021/bi400914c

Although several proteins postulated to be fatty acid transporters have now been shown to have other roles, the mechanistic roles of the protein CD36 have remained elusive and are widely debated.

After measuring the products of fatty acid metabolism over time, the researchers found that CD36 enhances fatty acid metabolism into triglycerides (fat deposits), without increasing fatty acid translocation across the membrane in a cell line that does not normally synthesize triglycerides. Thus, CD36 increases fatty acid uptake by increasing intracellular metabolism, which promotes diffusion of fatty acids into cells.

"Our study shows that fatty acid entry into cells occurs by diffusion without catalysis by a protein previously described as a fatty acid transport protein. However, this protein promotes intracellular metabolism and storage," said senior author James A. Hamilton, PhD, professor of physiology, biophysics and radiology at Boston University School of Medicine. "With this advance in basic science, new drugs can be designed that target the exact mechanism more precisely than currently available drugs." 

Citation: Su Xu, Anthony Jay, Kellen Brunaldi, Nasi Huang, and James A. Hamilton, 'CD36 Enhances Fatty Acid Uptake by Increasing the Rate of Intracellular Esterification but Not Transport across the Plasma Membrane', Biochemistry, 2013, 52 (41), pp 7254–7261
September 17, 2013 DOI: 10.1021/bi400914c