Transfer of fatty acids between intracellular membranes: roles of soluble binding proteins, distance, and time

Abstract

Soluble fatty acid binding proteins (FABPs) are thought to facilitate exchange of fatty acids between intracellular membranes. Although many FABP variants have been described, they fall into two general classes. "Membrane-active" FABPs exchange fatty acids with membranes during transient collisions with the membrane surface, whereas "membrane-inactive" FABPs do not. We used modeling of fatty acid transport between two planar membranes to examine the hypothesis that these two classes catalyze different steps in intracellular fatty acid transport. In the absence of FABP, the steady-state flux of fatty acid from the donor to the acceptor membrane depends on membrane separation distance (d) approaching a maximum value (J max) as d approaches zero. Jmax is one-half the rate of dissociation of fatty acid from the donor membrane, indicating that newly dissociated fatty acid has a 50% chance of successfully reaching the acceptor membrane before rebinding to the donor membrane. For larger membrane separations, successful transfer becomes less likely as diffusional concentration gradients develop. The mean diffusional excursion of the fatty acid into the water phase (d m) defines this transition. For dϽ Ͻd m, dissociation from the membrane is rate limiting, whereas for dϾ Ͼd m, aqueous diffusion is rate limiting. All forms of FABP increase d m by reducing the rate of rebinding to the donor membrane, thus maintaining J max over larger membrane separations. Membrane-active FABPs further increase J max by catalyzing the rate of dissociation of fatty acids from the donor membrane, although frequent membrane interactions would be expected to reduce their diffusional mobility through a membrane-rich cytoplasm. Individual FABPs may have evolved to match the membrane separations and densities found in specific cell lines.

Fatty acid binding protein is a major determinant of hepatic pharmacokinetics of palmitate and its metabolites

“…Luxon (24) showed that the cytoplasmic transport of 12-N-methyl-7-nitrobenzo-2-oxa-1,3-diazol-amino stearate is modulated by binding to soluble proteins like FABPs and that FABPs enhance diffusive transport by reducing binding to immobile cytosolic membranes. Weisiger and Zucker (42) have recently proposed a simple kinetic model for cytoplasmic diffusion and suggested that "membrane-active" FABPs are the soluble fatty acid binding proteins that enhance faster cytoplasmic diffusion of fatty acids. The correlation between PS for unchanged [ 3 H]palmitate and the L-FABP level (Fig.…”

Reduced hepatic extraction of palmitate in steatosis correlated to lower level of liver fatty acid binding protein

“…Luxon and co-workers (18) reported that 1) increasing the cytosolic concentration of L-FABP caused a parallel increase in the rate of cytoplasmic palmitate transport in clofibrate-treated male rats; and 2) whereas higher levels of membrane transporters may explain the increased rates of influx and efflux in clofibrate-treated male rats, L-FABP could also directly catalyze transfer of fatty acids to and from the inner surface of the plasma membrane through a collisional mechanism. Weisiger and Zucker (35) have recently proposed a simple kinetic model for cytoplasmic diffusion and suggested that "membrane-active" FABPs are the soluble FABP that enhance faster cytoplasmic diffusion of fatty acids. However, hepatic extraction of palmitate and other solutes may also be influenced by the albumin contents in the perfusate, perfusion flow rate, and vascular dispersion (28,34).…”

Mechanisms of Intracellular Fatty Acid Transport: Role of Cytoplasmic-Binding Proteins

“…This monograph addresses the transport functions of FABPs in intuitive terms. This topic has been addressed in more detail previously, and the reader is referred to these papers for a more comprehensive discussion (Weisiger 1998(Weisiger , 1999(Weisiger , 2002Weisiger and Zucker 2002).…”

“…Because the fatty acid never enters the water phase, this process requires much less energy and thus happens much more quickly. FABPs that have the ability to catalyze dissociation from membranes have been termed "membrane active," whereas those that lack this ability are "membrane inactive" (Weisiger and Zucker 2002). Liver FABP appears to be membrane inactive, whereas all other FABPs that have been studied for this ability seem to have the ability to catalyze dissociation.…”

“…Thus, the functions of FABPs may be viewed in terms of how they catalyze the transfer of fatty acids from one membrane to another (typically referred to as the "donor" and "acceptor" membranes). A complete analysis of this process has been published (Weisiger and Zucker 2002). Unfortunately, this analysis relies on mathematics and is thus not accessible to many investigators.…”