Functional mapping and characterization of the responsive region required for polyunsaturated fatty acid regulation in the rat fatty acid synthase gene
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Type and amount of dietary fats modify the onset of nutritionally related pathophysiologies such as diabetes mellitus, obesity and coronary heart disease. Among fats, arachidonic acid, 20:4(n-6) and docosahexaenoic acid, 22:6(n-3) are highly unsaturated long chain fatty acids (HUFA) that participate in abundant physiological events. The unique ability of HUFA to modulate lipid metabolism, and consequently energy homeostasis, depends on their coordinated effect on gene expression. HUFA inhibit the expression of genes responsible for fatty acid biosynthesis and at the same time stimulate the expression of genes involved in oxidative pathways and thermogenesis (Baillie et al., 1999; Jump and Clarke, 1999; Power and Newsholme, 1997). As a consequence, dietary HUFA improve insulin sensitivity and glucose utilization in skeletal muscle and adipose tissue (Baur et al., 1998; Pan et al., 1995; Storlien et al., 2000). This dissertation presents evidence of: a) the mapping and characterization of two candidate responsive regions required for HUFA regulation in the 5í flanking region of the rat fatty acid synthase (FAS), b) that the NF-Y and Sp1 sites in the proximal promoter of the FAS gene are essential for HUFA inhibition, c) that dietary HUFA inhibit the DNA binding of hepatic NF-Y and Sp1, and d) that there is a posttranslational mechanism implicated in this regulation. Identification of this two HUFA-DNA target sites open the possibilities to development of nutritional and pharmacological interventions in diabetes and obesity. Furthermore, it might allow us in the future to screen genetic mutations in humans and incorporate the appropriate preventive dietary changes to avoid the early onset of a metabolic disease.