Introduction How Do Long-Chain Free Fatty Acids Cross Cell Membranes?

Abstract

Long-chain, non-esterified free fatty acids (FFA), the building blocks from which triglycerides are synthesized, are important energy substrates in various tissues, essential building blocks for the lipid components of cell membranes, and precursors for the synthesis of important biological mediators such as the prostaglandins. They are also increasingly being recognized as important intracellular mediators of gene expression. These multiple roles suggest that careful regulation of all aspects of FFA disposition, including cellular uptake, would be advantageous. However, although the intracellular metabolism of FFA and their transport in plasma as complexes with albumin have been extensively studied, little attention was paid until recently to the mechanisms by which FFA enter and leave cells. This neglect occurred both for methodologic reasons and because the cellular uptake of FFA was long considered to be an entirely unregulated process in which FFA partitioned passively into the lipid bilayer of the plasma membrane.

Since 1981, a series of studies from several groups clarified the influence of albumin binding on the uptake kinetics of FFA and other bound ligands, making more detailed studies of the uptake process feasible (1-6). Once it became clear that FFA uptake occurred principally from the very small unbound ligand pool in plasma and not from the albumin-bound compartment, it was quickly reported that a major component of FFA uptake in certain cell types, including hepato-cytes, adipocytes, and cardiac and skeletal myocytes, in fact exhibited all the kinetic properties of a facilitated transport process: saturation, trans-stimulation, cis-inhibition, and counter transport (7-18). These observations, which—if valid—cannot be explained by purely passive diffusion, have suggested to many investigators the existence of a facilitated uptake process for FFA, which appears to exist in parallel with a nonsaturable, presumable diffusive pathway.