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Dietary docosahexaenoic acid (22:6n-3, DHA) has been shown to exert beneficial effects on coronary heart disease including the prevention of ischemia reperfusion injury. The ability to acutely infuse DHA to the heart to prevent ischemia reperfusion injury is a potentialy valuable tool in planned surgery where reperfusion and/or ischemia will take place including coronary artery bypass surgery and angioplasty. In the present study, hearts from chow-fed (AIN-93M) Sprague Dawley rats (male) 9-12 weeks of age were isolated and artificially perfused. The protocol included: 30 min stabilization period, 30 min global no flow ischemia, 15 min fatty acid infusion with reperfusion, and 75 min reperfusion in the absence of fatty acids. The fatty acid infusions included 10, 20, 40, 60, 80, 100 or 120 µM of either palmitate or DHA complexed to 3% essentially fatty acid free bovine serum albumin as well as a vehicle control. Heart functional data was recorded continuously and total heart infarct volume was determined after staining with triphenyltetrazolium chloride. DHA at 10µM significantly reduced the infarction area at the end of the reperfusion period compared to that observed in the10µM of palmitate and vehicle control conditions. Infarction areas after infusions with DHA or palmitate were similar to controls after 20-60 µM infusions and greater than controls after 80-120 µM infusions, except for the 100 µM palmitate conditions which were similar to the low and high doses. In this model of infusion, 120 µM of fatty acid was the maximum amount of DHA tolerated, as several hearts went into fibrillation and did not recover and failed to complete the reperfusion at concentrations greater than 120 µM of DHA. DHA and palmitate also exerted dose dependent effects on functional parameters. In summary, infusion of DHA and palmitate cause dose dependent effects on heart function.

Thesis--Wisconsin. / Vita. Includes bibliographical references (leaves 72-98).

Fatty acids are important regulators in the control of mammalian energy homeostasis. They are ingested in the diet but a significant amount are also endogenously produced by de novo lipogenesis. Fatty acid elongation beyond 16 carbons (palmitic acid) can occur to generate very long chain fatty acids (VLCFA), a process that is initiated by the rate-limiting condensation reaction. To date, six mammalian enzymes responsible for this reaction, ELOVL1-6 (Elongation of very long chain fatty acid), have been characterized. All of them exert substrate specificity and tissue-specific gene expression. In this thesis, factors that regulate fatty acid metabolism and, in particular, fatty acid synthesis and elongation will be presented. The enclosed papers discuss issues as to how Elovl3 is regulated in liver and in different adipose depots and what effects ablation of this enzyme causes to lipid homeostasis. Hepatic Elovl3 gene expression followed a circadian rhythm, present exclusively in sexually mature male mice. In contrast to the expression of several other lipogenic genes, Elovl3 gene expression was not affected by fasting or refeeding. Instead, the gene expression was influenced by steroid hormones such as glucocorticoids and sex hormones. Interestingly, despite reduced levels of leptin, Elovl3-ablated mice were shown to be resistant to diet induced weight gain, which seemed to be due to a decreased ratio between energy intake and energy expenditure. This phenotype was more pronounced in female mice. / At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 3: Manuscript.

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