Researchers find new links between obesity and cardiovascular disease.


Obesity-linked diabetes is a growing public health problem and contributes to cardiovascular disease, the most prevalent cause of death in the U.S. High plasma concentrations fatty acids derived from food intake and excess fat stores and high concentrations of glucose from diet are hallmarks of diabetes. Increasing attention has been directed to fatty acids and their multiple pathophysiological effects.

The plasma membrane receptor CD36 is a key protein that plays central roles in obesity and type 2 diabetes. It binds both fatty acids and oxidized low density lipoprotein (LDL), which has been implicated in promotion of atherosclerosis. However, the mechanistic roles of CD36 are complex and have remained elusive.

In an opensource study published in the Journal of Biological Chemistry, a research group from Boston University applied novel methods to detect binding of fatty acids to CD36 and their effect on internalization of oxidized LDL. Although other research groups have characterized a fatty acid binding site on CD36 and postulated CD36 to be a gatekeeper for fatty acid entry into cells, the lab previously found that CD36 did not increase fatty acid translocation across the plasma membrane.

In the current study all of the common dietary fatty acid types (saturated, unsaturated, trans and polyunsaturated) were shown by a new assay to bind to CD36 at levels greater than expected for a single binding site characterized in previous studies. In cells with CD36 present in the plasma membrane, all of the fatty acids also enhanced oxidized LDL uptake, except for the fish oil fatty acid DHA. This current study adds to the possible mechanisms for fish oil benefits that are now widely recognized.

Since obesity and type 2 diabetes are characterized by high plasma levels of fatty acids, the demonstrated enhancement of oxLDL uptake by increases in common dietary fatty acids may contribute to the pathophysiology of these diseases. The team summise that the new results provided a link between fatty acids, CD36, and atherosclerosis and new drugs can be designed that target the exact mechanism more precisely.

Source:  Boston University School of Medicine

 

Using homology modeling of CD36 from the recently published crystal structure of CD36 family member LIMP-2 (15), we designed this schematic showing a possible mechanism for oxLDL binding, after FA opens the binding site, based on combining our FA binding studies (SPR) and Dii-oxLDL binding/uptake data (microscopy). The site of FA and oxLDL binding is presumably on the opposite face of the CD36 protein structure (left side, as the CD36 protein is oriented in the schematic) from the disulfide bond-rich region (right), as we found disulfide bond reduction does not alter oxLDL binding. LDL is shown in the upper background with a single apolipoprotein B-100 wrapping the particle and white dots on the LDL indicate oxidation. One of the implications of the newly characterized FA sites on CD36 is that as the concentration of FA in the plasma and/or PM increases, the sites on CD36 will have high occupancy, further increasing oxLDL binding and uptake.  CD36 binds oxidized LDL in a mechanism dependent upon fatty acid binding.  Hamilton et al 2015.

Using homology modeling of CD36 from the recently published crystal structure of CD36 family member LIMP-2 (15), we designed this schematic showing a possible mechanism for oxLDL binding, after FA opens the binding site, based on combining our FA binding studies (SPR) and Dii-oxLDL binding/uptake data (microscopy). The site of FA and oxLDL binding is presumably on the opposite face of the CD36 protein structure (left side, as the CD36 protein is oriented in the schematic) from the disulfide bond-rich region (right), as we found disulfide bond reduction does not alter oxLDL binding. LDL is shown in the upper background with a single apolipoprotein B-100 wrapping the particle and white dots on the LDL indicate oxidation. One of the implications of the newly characterized FA sites on CD36 is that as the concentration of FA in the plasma and/or PM increases, the sites on CD36 will have high occupancy, further increasing oxLDL
binding and uptake. CD36 binds oxidized LDL in a mechanism dependent upon fatty acid binding. Hamilton et al 2015.

 

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