THE REGULATION OF FATTY ACID TRANSPORT AND TRANSPORTERS IN INSULIN-, AND CONTRACTION-STIMULATED SKELETAL MUSCLE

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THE REGULATION OF FATTY ACID TRANSPORT AND TRANSPORTERS IN INSULIN-, AND CONTRACTION-STIMULATED SKELETAL MUSCLE

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dc.contributor.advisor Bonen, Arend
dc.contributor.advisor Holloway, Graham
dc.contributor.author Jain, Swati
dc.date 2011-09-23
dc.date.accessioned 2011-09-26T17:40:46Z
dc.date.available 2011-09-26T17:40:46Z
dc.date.issued 2011-09-26
dc.identifier.uri http://hdl.handle.net/10214/3047
dc.description.abstract The clearance of circulating glucose and long-chain fatty acids (FA) into skeletal muscle involves the translocation of glucose transporter GLUT4, fatty acid translocase (FAT/CD36), plasma membrane associated fatty acid binding protein (FABPpm) and fatty acid transport protein (FATP) 1 and 4 to the plasma membrane (PM). FAT/CD36 also appears to participate in the regulation of mitochondrial FA oxidation. Metabolic challenges are known to increase FA transport and/or oxidation, but whether this is solely attributable to the translocation of FAT/CD36 to the sarcolemma and/or mitochondria is unknown. Moreover, the signaling and trafficking pathways involved in the translocation of FA transporters are largely unexplored. In this thesis it was found that FA transport was markedly increased following insulin (+2.9-fold) or contraction (+1.7-fold) stimulation of skeletal muscle, along with the PM contents of FAT/CD36 (+78%, +55%,), FABPpm (+61%, +62%), FATP1 (+84%, +61%) and FATP4 (+60%, +66%) (p<0.05). Upon combining the two stimuli, only the translocation of FAT/CD36 (+179%) and FATP1 (+125%) to the PM was additive, suggesting that these transporters may reside in distinct insulin-sensitive and contraction-sensitive intracellular compartments. The translocation of FA transporters may involve the insulin-signaling protein Akt2. It was found that insulin-stimulated FA transport and PM translocation of FA transporters was essentially prevented in Akt2 knockout mice. Following contraction, FA transport was also markedly blunted, along with an impaired translocation of both FAT/CD36 and FATP1, but not FABPpm or FATP4. FA oxidation and mitochondrial FAT/CD36 appearance were also inhibited following muscle contraction in knockout mice (p<0.05). Whether the GLUT4 trafficking protein Munc18c is important for the vesicular re-distribution of FA transporters to the PM or mitochondria was also investigated. FA uptake was comparably increased 1.4 fold with insulin and contraction in both wildtype and heterozygous Munc18c-/+ mice, as were PM FA transporters FAT/CD36 (+82%, +84%), FABPpm (+39%, +43%), FATP1 (+40%, +38%) and FATP4 (+33%, +32%) (p<0.05). Contraction-stimulated mitochondrial FA oxidation was also increased similarly in wildtype (+39%) and Munc18c-/+ mice (+33%). These studies demonstrate that a number of FA transporters are involved in upregulating skeletal muscle FA transport, although their signaling and trafficking pathways may differ from that of GLUT4. en_US
dc.language.iso en en_US
dc.subject FAT/CD36 en_US
dc.subject FABPpm en_US
dc.subject FATP en_US
dc.subject fatty acid transport en_US
dc.subject glucose transport en_US
dc.title THE REGULATION OF FATTY ACID TRANSPORT AND TRANSPORTERS IN INSULIN-, AND CONTRACTION-STIMULATED SKELETAL MUSCLE en_US
dc.type Thesis en_US
dc.degree.programme Human Health and Nutritional Sciences en_US
dc.degree.name Doctor of Philosophy en_US
dc.degree.department Department of Human Health and Nutritional Sciences en_US


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