Free Fatty Acids Carried by Lipoproteins: Revisiting the Overlooked Cargo

ABSTRACT Free fatty acids (FFAs) are hydrophobic and therefore cannot enter the bloodstream at appreciable levels unless they are solubilized by FFA carriers. Albumin has been appreciated for years as the major FFA carrier, but it is not the only carrier. While the cholesterol and triacylglycerol components of lipoproteins are measured clinically, there are other bioactive lipids present in lipoproteins as well. There is strong evidence showing that multiple lipoprotein classes carry FFAs, and some evidence indicates potential physiological roles of lipoprotein‐bound FFAs. Apolipoproteins and other lipoprotein‐associated proteins may be responsible for FFA binding to lipoprotein particles, as lipoproteins contain numerous proteins that are predicted to have multiple FFA binding sites. Lipoproteins isolated from plasma contain FFAs, and the FFA loading appears to be driven in part by mass action when the FFA level is elevated as well as by low albumin abundance in cases of severe hypoalbuminemia. When the FFA levels rise on lipoproteins, through effects on cholesterol ester transfer protein, the lipoprotein profile may be altered. FFA binding to lipoproteins may also protect the lipoproteins from oxidative damage. The contribution of lipoproteins to FFA flux through the circulation is less clear but may play a particularly important role when albumin expression is low to drive the recruitment of this secondary FFA carrier system. In recent decades research progress has slowed in this area, leaving major knowledge gaps to address. The remaining need for research is discussed, and the physiological implications of lipoprotein‐bound FFAs are discussed in this review.