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The Role of Protein Mediated Transport in Regulating Mitochondrial Long Chain Fatty Acid Oxidation
| Content Provider | Semantic Scholar |
|---|---|
| Author | Holloway, Graham P. |
| Copyright Year | 2007 |
| Abstract | THE ROLE OF PROTEIN MEDIATED TRANSPORT IN REGULATING MITOCHONDRIAL LONG CHAIN FATTY ACID OXIDATION Graham Paul Holloway Advisor: University of Guelph, 2007 Professor L.L. Spriet This thesis is an investigation of the role of fatty acid translocase (FAT/CD36), plasma membrane associated fatty acid binding protein (FABPpm) and carnitine palmitoyltransferase I (CPTI) in transporting long chain fatty acids (LCFA) across mitochondrial membranes. Maximal CPTI activity, as well as the sensitivity of CPTI for its substrate palmitoyl-CoA (P-CoA) and its inhibitor malonyl-CoA (M-CoA), were measured in mitochondria isolated from human vastus lateralis muscles at rest and following muscle contraction. Exercise did not alter maximal CPTI activity, or the sensitivity of CPTI for P-CoA. In contrast, exercise progressively attenuated the ability of M-CoA to inhibit CPTI activity. Mitochondrial FAT/CD36 protein content was also measured at rest, during, and following 2 hours of cycling at ~60% maximal oxygen uptake. Exercise progressively increased the content of mitochondrial FAT/CD36 (+59%), which was significantly (P<0.05) correlated with palmitate oxidation during exercise (r=0.52), while palmitate oxidation was inhibited ~80% by the administration of a specific FAT/CD36 inhibitor. These data suggest that alterations in CPTI M-CoA sensitivity and increases in mitochondrial FAT/CD36 coordinate exercise induced increases in fatty acid oxidation. FABPpm, another plasma membrane transport protein, has identical amino acid sequence to mitochondrial aspartate aminotransferase (mAspAT). Since FABPpm contributes to plasma membrane fatty acid transport, the role of FABPpm with respect to mitochondrial LCFA transport was investigated. However, unlike FAT/CD36, muscle contraction did not induce an increase in mitochondrial FABPpm protein in rat or human skeletal muscle. In addition, electrotransfecting FABPpm cDNA into rat skeletal muscle upregulated this protein in mitochondria +80% without altering mitochondrial palmitate oxidation. In contrast, electrotransfection increased mAspAT activity +90%, and this was correlated (r=0.75; P<0.01) with FABPpm protein. These data suggest that FABPpm does not contribute to the regulation of mitochondrial LCFA transport. Previously, it has been suggested that mitochondria from obese individuals contains an inherent dysfunction to oxidize LCFAs. In age matched lean (BMI = 23.3±0.7 kg⋅m) and obese (BMI = 37.6±2.2 kg⋅m) individuals, isolated mitochondrial palmitate oxidation was not altered. In addition, mitochondrial FAT/CD36 content were not different in lean and obese individuals. In contrast, citrate synthase and betahydroxyacyl-CoA dehydrogenase, common markers of total mitochondrial content, were decreased with obesity. Therefore, the decrease in mitochondrial content appeared to account for the observed reductions in whole muscle LCFA oxidation. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www.uoguelph.ca/hhns/grad/pdf_theses/HollowayPhDThesis.pdf |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Acetyl-CoA C-Acyltransferase Amino Acid Sequence Amino Acids Aspartate Transaminase Aspartic Acid Brain–computer interface Carnitine O-Palmitoyltransferase Carrier Proteins Citrate (si)-Synthase Eighty FAT1 gene FAT1 protein, human Fatty Acid-Binding Proteins Fatty Acids Fatty acid glycerol esters Fifty Nine File Allocation Table GFP-cDNA Graham scan Long-Chain-Acyl-CoA Dehydrogenase Maximal set Membrane Transport Proteins Mitochondria Mitochondrial Aspartate Aminotransferase Mitochondrial Diseases Mitochondrial Inheritance Mitochondrial Membranes Muscle Contraction Obesity Oxygen Palmitoyl-CoA Hydrolase Plasma Active Plasma membrane Platelet Glycoprotein 4, human Skeletal muscle structure Structure of vastus lateralis muscle Transaminases Transmembrane Transport acyl-CoA dehydrogenase fatty acid oxidation fatty acid transport palmitate sodium citrate |
| Content Type | Text |
| Resource Type | Article |
