Review Long-chain fatty acid uptake and FAT/CD36 translocation in heart and skeletal muscle Debby P.Y. Koonen a,1 , Jan F.C. Glatz a , Arend Bonen b , Joost J.F.P. Luiken a,c, * a Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, NL-6200 MD Maastricht, The Netherlands b Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1 c Department of Biochemical Physiology and Institute of Biomembranes, Utrecht University, Utrecht, The Netherlands Received 19 April 2004; received in revised form 18 August 2005; accepted 30 August 2005 Available online 15 September 2005 Abstract Cellular long-chain fatty acid (LCFA) uptake constitutes a process that is not yet fully understood. LCFA uptake likely involves both passive diffusion and protein-mediated transport. Several lines of evidence support the involvement of a number of plasma membrane-associated proteins, including fatty acid translocase (FAT)/CD36, plasma membrane-bound fatty acid binding protein (FABPpm), and fatty acid transport protein (FATP). In heart and skeletal muscle primary attention has been given to unravel the mechanisms by which FAT/CD36 expression and function are regulated. It appears that both insulin and contractions induce the translocation of intracellular stored FAT/CD36 to the plasma membrane to increase cellular LCFA uptake. This review focuses on this novel mechanism of regulation of LCFA uptake in heart and skeletal muscle in health and disease. The distinct signaling pathways underlying insulin-induced and contraction-induced FAT/CD36 translocation will be discussed and a comparison will be made with the well-defined glucose transport system involving the glucose transporter GLUT4. Finally, it is hypothesized that malfunctioning of recycling of these transporters may lead to intracellular triacylglycerol (TAG) accumulation and cellular insulin resistance. Current data indicate a pivotal role for FAT/CD36 in the regulation of LCFA utilization in heart and skeletal muscle under normal conditions as well as during the altered LCFA utilization observed in obesity and insulin resistance. Hence, FAT/CD36 might provide a useful therapeutic target for the prevention or treatment of insulin resistance. D 2005 Elsevier B.V. All rights reserved. Keywords: Long-chain fatty acid uptake; FAT/CD36; Insulin; PI(3)K; Contraction; GLUT4 1. Introduction In skeletal muscle and heart, the oxidation of long-chain fatty acids (LCFA) provides much of the energy needed for proper function. Since intramuscular storage sites are a limited source, these tissues rely heavily on the continuous supply of exogenous LCFA mainly derived from adipose tissue. Al- though the single-pass extraction of albumin-bound LCFA from the circulation is very efficient in both heart [1] and muscle [2,3], LCFA uptake into these tissues involves the passage of LCFA across many barriers, as reviewed previously [1,4,5]. The plasma membrane is the final barrier to be crossed before LCFA reach the interior of the muscle cells (i.e., the cytoplasm), where LCFA transfer between intracellular mem- branes is facilitated by binding to soluble fatty acid-binding proteins (FABPc) [6,7]. Specifically, the predominant FABP isoform in muscle tissues, heart-type FABPc (H-FABPc) is 1388-1981/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.bbalip.2005.08.018 Abbreviations: ACC, acetyl-CoA carboxylase; AICAR, 5V -aminoimidazole- 4-carboxamide 1-h-d-ribofuranoside; AMPK, adenosine monophosphate (AMP)-activated protein kinase; Akt/PKB, protein kinase B; cAMP, adenosine 3V :5V -cyclic monophosphate; DAG, diacylglycerol; FABPc, cytoplasmic fatty acid-binding protein; FABPpm, plasmalemmal fatty acid-binding protein; FAT/ CD36, fatty acid translocase; FATP, fatty acid transport protein; IBMX, 3- isobutyl-1-methylxanthine; LCFA, long-chain fatty acid; MAPK, mitogen- activated protein kinase; PDE, phosphodiesterase; PKA, protein kinase A; PKC, protein kinase C; PL, phospholipids; PI(3)K, phosphatidylinositol-3-OH- kinase; TAG, triacylglycerol; TfR, transferrin receptor; VLACS, very long- chain acyl-CoA synthethase * Corresponding author. Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, NL-6200 MD Maastricht, The Netherlands. Tel.: +31 43 388 1209/1998; fax: +31 43 388 4574. E-mail address: j.luiken@gen.unimaas.nl (J.J.F.P. Luiken). 1 Current address: Department of Pediatrics, University of Alberta, Edmonton, Canada T6G 2S2. Biochimica et Biophysica Acta 1736 (2005) 163 – 180 http://www.elsevier.com/locate/bba