Regulation of fatty acid transporters in mammalian cells

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Introduction

Long chain fatty acids play a variety of roles in multicellular organisms. They are the major source of energy for the heart, and most tissues are able to oxidize free fatty acids (FFAs)1 for some portion of their energy requirements. In addition to their role as a fuel, FFAs are essential components of cellular membranes. The composition of fatty acids in membrane phospholipids has a large effect on membrane fluidity and functions such as transport and signal transduction. Fatty acids are also precursors for various lipid signaling molecules produced via the cyclooxygenase, lipoxygenase and epoxygenase pathways. The resultant lipid second messengers exert their effect through cell-surface and intracellular receptors and play a role in numerous physiological processes from blood clotting to childbirth, and the complexity of their functions is only beginning to be understood.

One aspect of fatty acid metabolism that is poorly understood is the process by which fatty acids are taken into cells. While the relative importance of diffusional versus protein-mediated mechanisms has yet to be determined, it is clear that when presented at high concentrations FFAs can diffuse across biological membranes at rates sufficient to support metabolism. However, since under physiological conditions FFAs are presented to cells at low concentrations, the search for proteins that efficiently mediate transbilayer movement has been undertaken by a number of laboratories and several candidates have been identified [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14]. Several recent reviews have focused on the controversy of whether the mechanism of transbilayer movement is either diffusional or protein-mediated [15], [16], [17], [18], [19]. The purpose of this review is not to restate the issues concerning diffusional versus protein mediated transport, but to outline the properties of the major putative transport proteins and to discuss the regulation of their expression. It is hoped that a greater understanding of the regulation of these proteins may lead to new insights into their physiological functions in fatty acid metabolism and possibly lead to conclusions concerning their role(s) in FFA transport.

Section snippets

Fatty acid flux in the fed versus the fast state

Dietary triglycerides (TG), digested by gastric and pancreatic enzymes are emulsified with bile salts in the digestive tract. Such fatty acids are internalized by intestinal epithelial cells and reesterified into TGs. Newly formed TGs are combined with cholesterol esters, phospholipids and lipoproteins to form chylomicrons which leave the intestines via lymph ducts and are released into the venous system. Upon entering the circulation, the TGs are hydrolyzed by endothelial lipoprotein lipase,

Mechanism of fatty acid uptake

Although the metabolic utilization and corporeal mobilization of FFAs has been intensively studied, the mechanism by which FFAs enter cells and the regulation of this process is less well understood. FFAs, poorly soluble in the aqueous environment of the blood plasma and interstitial fluid, are largely bound to albumin via several high-affinity fatty acid binding sites. Given the binding affinity of albumin for fatty acids and the equilibrium concentration of total fatty acids, the plasma free

Plasma membrane fatty acid binding protein (FABPpm)

The first putative fatty acid transporter to be identified was initially isolated from solubilized rat liver plasma membranes and jejunal microvillous membranes by Berk and collaborators [1], [2]. The key feature of the purification, oleate-agarose affinity chromatography, identified a 40 kDa plasma membrane fatty acid binding protein termed FABPpm. By using a combination of immunochemical and molecular analyses, FABPpm was shown to be expressed on the plasma membrane of liver, adipose tissue,

Plasma membrane fatty acid binding protein (FABPpm)

The peroxisome proliferator-activated receptor (PPAR) nuclear hormone receptors are a subfamily of the steroid hormone receptor superfamily which have been shown to be important in the regulation of many genes involved in lipid metabolism [110], [111], [112], [113], [114], [115], [116], [117], [118], [119], [120], [121], [122], [123], [124], [125], [126], [127], [128]. The three PPAR subtypes, PPARα, PPARδ (also known as NUC1, FAAR, or PPARβ) and PPARγ2

Concluding remarks

A more complete understanding of fatty acid transport is critical for not only the description of the processes of normal metabolism but also for the understanding of the pathophysiology behind such diseases as type 2 diabetes mellitus. Examining the commonalities and differences between regulation of the various putative transporters may lead to insight into their functions (see Table 4).

All three putative transporters are regulated to some degree by members of the PPAR family of transcription

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