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

Abstract

Cytosolic binding proteins are ubiquitous, yet their functions have been poorly defined. Research in multiple labs has now clarified two major transport functions for fatty acid binding proteins (FABPs), one of the most commonly studied examples of this diverse class. Most cellular fatty acids are bound to membranes. Because fatty acids are almost insoluble in water, their movement across the water between cellular membranes is very slow without FABP. FABP increases this rate by increasing the solubility of fatty acids in water. Many forms of FABP can also increase this rate by catalyzing release of the fatty acids from membranes. The first function is most valuable over longer distances (e.g., >1 microm in rat liver cells), while the second is most valuable for shorter distances. Thus, FABPs serve complementary intracellular transport functions. These conclusions may apply to other cytosolic proteins that bind poorly-soluble molecules.

Mechanistic Insight from In Silico Pharmacokinetic Experiments: Roles of P-glycoprotein, Cyp3A4 Enzymes, and Microenvironments

“…The HME may map in part to these subcellular structures. We suggest that the movement logic used by SAQ to change zones, especially movement between Z0 and Z6, may map to saquinavir binding to mobile components of one or more intracellular transport system, such as the fatty acid transport system (Weisiger, 2007). If future evidence supports that mapping, then the ISECC transport results can be taken as predictions that the carrier mechanism(s) will be saturated at higher saquinavir doses.…”

“…Zones map to intracellular gradients and microenvironments. A zone could, for example, map to a compound transport pathway (Weisiger, 1996(Weisiger, , 2002(Weisiger, , 2007, nucleus (Tran et al, 2003), mitochondria (Khoo et al, 2002), or a portion of the endoplasmic reticulum. Being below the level of resolution, their shape is indeterminate.…”

“…These movements, including the effective shortcut from Z0 to Z6, may map to any of a variety of yet unidentified micromechanisms. Plausible examples include saquinavir binding (somewhat preferentially) to a saturable component of a transcellular transport system, for example, fatty acid intracellular transport system described by Weisiger (1996Weisiger ( , 2002Weisiger ( , 2007, or becoming associated (somewhat preferentially) with a nonequilibrium, apically directed intracellular flux of the type described by Kurakin (2009).…”

Identification of intracellular carriers for the endocannabinoid anandamide

“…It is expected to be more efficient than the free diffusion of AEA across the cytosol or the movement of endocytic vesicles. For example, cytosolic free diffusion of AEA is expected to be a relatively slow process, as the structurally related stearate requires up to 200 seconds to diffuse half-way across the cytosol of a 20-m hepatic cell (54,55).…”

The Role of Intestinal Fatty Acid Binding Proteins in Protecting Cells from Fatty Acid Induced Impairment of Mitochondrial Dynamics and Apoptosis

“…Among others, liver FABP (L-FABP) is also expressed in the intestine along with IFABP, though the expression of IFABP is more prevalent than that of LFABP [11]. FABPs are a class of fatty acid transport proteins that ferry ligands to different subcellular compartments for the FA utilization and metabolism [12][13][14]. Extensive research has been devoted to explore the conformational changes and ligand binding affinities in vitro [15,16].…”