The Evolution of Gemomic and Non-Genomic Regulatory Mechanisms o fMitochondrial Lipid Oxidation in Fish

Abstract

<p>Research in the field of lipid metabolism has blossomed in recent decades, particularly in terms of human metabolic disease. This has been studied mostly in mammals despite the importance of lipid metabolism on the energetics and life history of non-mammalian vertebrates such as fish. Fish have a large ecological and economic impact but have received little attention in the area of lipid metabolism. The main goal of my thesis is to understand the regulatory mechanisms which control lipid oxidation in fish under changing physiological conditions. In particular, I investigated the regulation of carnitine palmitoyltransferase (CPT) I, an enzyme which controls the entry of fatty acids into the mitochondria for oxidation. To accomplish this, I first examined the function and regulation of CPT I under routine conditions in liver and muscle tissue of rainbow trout. The results indicated that the expression, function and regulation of CPT I was variable across tissues. A phylogenetic reconstruction revealed multiple CPT I isoforms arising in fish after diverging from mammals highlighting the need for future tissue and species specific investigations.</p> <p>With this fundamental knowledge, I was able to determine the effects of dietary manipulations and fasting on genomic and non-genomic CPT I regulation in rainbow trout. I found that changes in dietary fatty acids mainly effect the genomic regulation of CPT I through changes in the expression of CPT I and its transcription factor, PPAR. Fasting also induced increases in PP AR expression and further, caused a reduction in CPT I sensitivity to its inhibitor, malonyl-CoA, resulting in higher CPT I activity and rates of fatty acid oxidation.</p> <p>In a final comparative study, I investigated the individual effects of endurance exercise on muscle fatty acid oxidation in rainbow trout and the combined effects of endurance exercise and fasting in a natural population of migrating pacific salmon. I found that changes in the activity of several lipid oxidation enzymes in red muscle during exercise were not as great as those found in the initial stages of migration in salmon. Similarly, changes in CPT I mRNA expression were greater in migrating salmon than in exercised trout. In contrast, changes in the mRNA expression of metabolic regulators and transcription factors were similar in both exercising trout and migrating salmon. This thesis has significantly advanced our knowledge of lipid metabolism in fish and has highlighted the need to future research in this area.</p>