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  • There are two ways to transport FFAs into cells


    There are two ways to transport FFAs into cells. First by passive diffusion. Second as the putative long-chain fatty G-36 transporters are proposed, CD36 the plasma membrane-associated fatty acid-binding protein (FABPpm) and fatty acid transport proteins (FATP) [11], where CD36 is responsible for uptake G-36 of majority of LCFA. Glucose is of hydrophilic nature, and hence the lipid bilayer of plasma membrane is impermeable for it. Therefore, glucose transport across the plasma membrane is mediated via glucose transporters. In humans there are three classes of glucose transporters: GLUTs (the facilitative glucose transporters), SGLTs (the sodium-glucose cotransporters, and SWEETs (Sugars Will Eventually be Exported Transporters) [52].
    Characteristics of human glucose transporters Facilitative glucose transporters belong to the major facilitator super family, which is a group of transmembrane proteins that transport a wide range of solutes. This super family includes thousands of sequenced members and is present in organisms ranging from bacteria to human. In human, 14 members of the mammalian glucose transporters (GLUT) family GLUT1–GLUT12, GLUT14, and HMIT (GLUT13) have been identified [12]. They are encoded by genes SLC2A. The GLUT proteins contain 12 hydrophobic α-helical transmembrane domains. The cytoplasmic domain contains a short N-terminal segment, a large C-terminal segment, a large intracellular loop between transmembrane domains 6 and 7, and a single N-linked oligosaccharide moiety. The sequences among the members of the family are 14%–63% identical and 30%–79% conservative [13]. The GLUT proteins differ in tissue-specific expression. In addition to GLUT family, members of the sodium glucose cotransporter (SGLT) family are widely present, as they transport a variety of substrates. Human plasma membrane proteins encoded by SLC5A genes are Na+/substrate cotransporters. These cotransporters transport sugars, inositols, lactate, choline, urea, proline, and ions such as iodide. The SGLT1 may act as a water transporter. The SGLTs are encoded by SLC5 genes. There are 12 human genes in the SLC5 gene family. The sequences among the members of the family are 21%–70% identical to the amino acids of SGLT1. On the other hand, there is diversity in gene structure. In 8 genes coding sequences are found in 14–15 exons (SLC5A1, SLC5A2, SLC5A4–SLC5A6, and SLC5A9–SLC5A11), for SLC5A3 and SLC5A7 are contained in 1 and 8 exons, respectively. In SLC5A3 and SLC5A9–SLC5A11 there is evidence of alternative splicing [19]. The human SLC5 genes are predicted to code for 60–80kDa proteins containing between 580 and 718 residues. The SGLT proteins contain 14 transmembrane helices but NIS (encoded by SLC5A5 gene) and SMCT1 (encoded by SLC5A8 gene), lack the 14th transmembrane helix [55]. The N-terminus is located on the extracellular side of the membrane and there are a variable number of consensus sites for N-linked glycosylation [19]. The SWEETs, encoded by SLC50 genes, are a new class of glucose transporters, recently identified thale cress in plant (Arabidopsis thaliana). Homologs of these transporters are also widespread in human and animals. Animals have only one SWEET however, Caenorhabditis elegans, the round worm has seven SLC50A genes [54], [57], [58]. There is a single homolog in the human genome (SWEET1), encoded by SLC50A1 gene [19]. This class of transporters is predicted to have 7 transmembrane helices. In human, this transporter did not promote glucose uptake. It mediates a weak efflux. Human SWEET1 is predominantly expressed in the Golgi apparatus and minimal expression was found in the plasma membrane. The highest levels of SWEET expression were observed in oviduct, epididymis and intestine [19]. Expression of human SWEET1 was not observed in heart.
    Glucose transporters in healthy human heart The major isoform in human heart is GLUT4, which represents approximately 70% of glucose transporters [14]. Recent results suggest that other members of GLUTs have also been reported in human heart. These proteins are: GLUT1, GLUT3, GLUT8, GLUT10, GLUT11, and GLUT12 [9] (Table 1). Although all of the mentioned transporters are expressed in human heart, there are differences in the expression of these transporters depending on the development. In the embryonic and early neonatal heart, GLUT1 is the predominant glucose transporter, which in basal conditions is located mainly in the sarcolemma. In the adult heart, the expression of GLUT1 is regulated by chronic hypoxia [15] and long-term fasting [16]. The GLUT1 approximately account for 40% of cardiac glucose transporters [10]. The GLUT1 is responsible for basal cardiac glucose transport. After birth, GLUT1 is downregulated and GLUT4 is rapidly upregulated. In the newborn and the adult heart, GLUT4 is the main glucose transporter [9]. In basal conditions it is located mainly in intracellular membrane compartments. In response to stimuli, such as ischemia, catecholamines, insulin, etc., GLUT4 is translocated to the cell surface. In this way, glucose transport into the cardiomyocytes increases 10- to 20-fold. It was found in animal studies, using a canine model, that GLUT4 protein content is significantly higher in the atria as compared to ventricles. The highest content of GLUT4 was observed in the right atrium in comparison to the left atrium [38]. In the adult heart, the expression of GLUT 1 is regulated, for example, by chronic hypoxia [15], as well as by long-term fasting [16]. Like GLUT1, the expression of GLUT4 is regulated by different stimuli such as insulin depletion [9], fatty acids [17], and thyroid hormone [52].