Cellular uptake and intracellular trafficking of long chain fatty acids

Abstract

While aspects of cellular fatty acid uptake have been studied as early as 50 years ago, recent developments in this rapidly evolving field have yielded new functional insights on the individual mechanistic steps in this process. The extremely low aqueous solubility of long chain fatty acids (LCFA) together with the very high affinity of serum albumin and cytoplasmic fatty acid binding proteins for LCFA have challenged the limits of technology in resolving the individual steps of this process. To date no single mechanism alone accounts for regulation of cellular LCFA uptake. Key regulatory points in cellular uptake of LCFA include: the aqueous solubility of the LCFA; the driving force(s) for LCFA entry into the cell membrane; the relative roles of diffusional and protein mediated LCFA translocation across the plasma membrane; cytoplasmic LCFA binding protein-mediated uptake and/or intracellular diffusion; the activity of LCFA-CoA synthetase; and cytoplasmic protein mediated targeting of LCFA or LCFA-CoAs toward specific metabolic pathways. The emerging picture is that the cell has multiple, overlapping mechanisms that assure adequate uptake and directed intracellular movement of LCFA required for maintenance of physiological functions. The upcoming challenge is to take advantage of new advances in this field to elucidate the differential interactions between these pathways in intact cells and in tissues. -McArthur, M.

Calculation of apparent pKavalues of saturated fatty acids with different lengths in DOPC phospholipid bilayers

“…In this section, we present density profiles, hydrogen bonding capabilities and free energy profiles of free fatty acids, separately for neutral and anionic form in the DOPC bilayer. Both forms exist in yet undetermined ratio in the bilayer, depending on their pKa value which is different than pKa values in water due to hydrophobic environment of the bilayer, 15 and are equally important for theoretical determination of their acidity using equations ( 1) and (2). Figure 1 shows number density profiles for myristic (C14:0), palmitic (C16:0) and stearic acid (C18:0) in neutral and anionic forms, respectively, immersed in DOPC bilayer after 200 ns of simulation.…”

“…An adequate intake of free long-chain fatty acids (FFA) is essential for cells and organism growth and development. 1,2 FFAs can easily flip-flop across the bilayer in their neutral form according to the concentration gradient and without the need for protein assistance. [3][4][5][6][7] On the other hand, the transport of the anionic form is far more difficult and has not been experimentally detected since the energy penalty for bringing the charged molecule across the bilayer is very high and is probably assisted by the cellular membrane protein machinery, in particular uncoupling proteins (UCPs).…”

Saturated fatty acids accelerate linear motility through mitochondrial ATP production in bull sperm

“…Although fatty acids are essential nutrients for cellular functions, 29 their transport across the plasma membrane in sperm is not well understood. There is evidence that the uptake of protein‐facilitated fatty acids is the key pathway in metabolic tissues, including the liver, adipose tissue, and muscle 30,31 .…”

Very long chain n-3 and n-6 polyunsaturated fatty acids bind strongly to liver fatty acid-binding protein

“…There is evi-dence that FABPs may influence fatty acid metabolism through facilitating uptake, transport, sequestration, and/ or metabolic targeting of fatty acids (11,12). Overexpression of L-FABP in fibroblasts stimulates cellular uptake of fatty acid and esterification of fatty acid into specific lipid classes (13,14). L-FABP may thus direct transport of fatty acids to various cellular targets (15).…”