Interactions Between Fatty Acid Transport Proteins, Genes That Encode for Them, and Exercise: A Systematic Review AVINDRA F. JAYEWARDENE, 1 * YORGI MAVROS, 1 ANNELIESE REEVES, 1 DALE P. HANCOCK, 2 TOM GWINN, 1 AND KIERON B. ROONEY 1 1 Discipline of Exercise and Sport Science, Faculty of Health Sciences, University of Sydney, Lidcombe, New South Wales, Australia 2 School of Molecular Biosciences, Faculty of Science, University of Sydney, Camperdown, New South Wales, Australia Long-chain fatty acid (LCFA) movement into skeletal muscle involves a highly mediated process in which lipid rafts are utilized in the cellular membrane, involving numerous putative plasma membrane-associated LCFA transport proteins. The process of LCFA uptake and oxidation is of particular metabolic significance both at rest and during light to moderate exercise. A comprehensive systematic search of electronic databases was conducted to investigate whether exercise alters protein and/or gene expression of putative LCFA transport proteins. There were 31 studies meeting all eligibility criteria, of these 13 utilized an acute exercise protocol and 18 examined chronic exercise adaptations. Seventeen involved a study design incorporating an exercise stimulus, while the remaining 14 incorporated a combined exercise and diet stimulus. Divergent data relating to acute exercise, as well as prolonged exercise training (3 weeks), on protein content (PC) response was identified for proteins CD36, FABP pm and CAV1. Messenger ribonucleic acid (mRNA) data did not always correspond to functional PC, supporting previous suggestions of a disconnect due to potentially limiting factors post gene expression. The large array of study designs, cohorts, and primary dependent variables within the studies included in the present review elucidate the complexity of the interaction between exercise and LCFA transport proteins. Summary of the results in the present review validate the need for further targeted investigation within this topic, and provide an important information base for such research. J. Cell. Physiol. 9999: 1–17, 2016. ß 2015 Wiley Periodicals, Inc. Long-chain fatty acid (LCFA) movement into skeletal muscle was thought to occur via passive diffusion. Recent studies have identified that uptake is the work of a highly mediated process in which lipid rafts are utilized in the cellular membrane, involving numerous LCFA transport proteins. The putative proteins involved in the process include cluster of differentiation 36 (CD36)/fatty acid translocase (FAT), plasma membrane-associated fatty acid binding protein (FABP pm ), fatty acid transport proteins 1–6 (FATP1-6) and caveolins 1–3 (CAV1-3; defining protein constituents of caveolae) (Abumrad et al., 1993; Hirsch et al., 1998; Trigatti et al., 1999; Kiens, 2006). Although not all are present in skeletal muscle (FATP2, FATP3, FATP5, and CAV2) (Hirsch et al., 1998), the interdependent nature of all fatty acid (FA) transporters within the human body dictate that assessment of these proteins are key when investigating periods of metabolic flux that alter LCFA metabolism (including exercise, caloric restriction, disease pathophysiology etc.), particularly as the process of LCFA uptake and oxidation in the mitochondria requires a cohesive network to transport from adipose tissue, through the endothelium, interstitial space, plasma membrane, cytosol, and mitochondrial membranes. The process of LCFA uptake and oxidation is of particular metabolic significance both at rest and during light to moderate exercise, where LCFA is the predominant substrate source for ATP re-synthesis (van Loon et al., 2001; Kiens, 2006). During aerobic exercise, there is an increase in LCFA release from adipose tissue to accommodate for the increased energy requirements of exercise (Dyck and Bonen, 1998). Chronically, endurance exercise training is characterized by both (i) a preferential switch to fat oxidation and esterification at both rest and during low to moderate intensity exercise, commonly referred to as “carbohydrate sparing” (Kiens, 2006) and (ii) increased intramyocellular triacylglycerol (IMTG) accumulation (Kiens, 2006). Although the increased fat oxidation is partially explained by the well-described increases in enzymes associated with FA oxidation (Gollnick and Saltin, 1982; Dyck et al., 2000; Bonen et al., 2006), it is also facilitated by increased LCFA transporter expression (Kiens, 2006; Glatz et al., 2010). In addition, as the concentration of circulating FAs does not change post-training, the increase in IMTG could be primarily dependent on the upregulation of FA transport protein action (Glatz et al., 2010). Numerous data in both animal and human models support a mechanism of protein translocation (from the cytoplasm to the plasma membrane) of CD36, FABP pm , FATP1, and FATP4 Conflicts of interest: The authors declare that they have no conflict of interest. Contract grant sponsor: Australian Postgraduate Award Scholarship. Contract grant sponsor: CRN in Advancing Exercise and Sport Science. *Correspondence to: Avindra F. Jayewardene, Exercise and Sport Science, Faculty of Health Sciences, The University of Sydney, 75 East St, Lidcombe, NSW, 2141, Australia. E-mail: ajay5611@uni.sydney.edu.au Manuscript Received: 3 December 2015 Manuscript Accepted: 4 December 2015 Accepted manuscript online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2016. DOI: 10.1002/jcp.25281 REVIEW ARTICLE 1 Journal of Journal of Cellular Physiology Cellular Physiology © 2015 WILEY PERIODICALS, INC.