Dietary fat has been linked to several diseases including insulin resistance, obesity, hypertension, atherosclerosis and certain types of cancers. Both the quantity and type of dietary fat contribute to the development and progression of these diseases. Recent experimental evidence indicates that the effect of fat is directed at the cellular level and involves both rapid and adaptive processes. Our studies have focused on the well-known suppression of hepatic lipogenesis by dietary polyunsaturated fatty acids (PUFA). PUFA effects on hepatic lipogenesis contribute to the decline in very low density lipoprotein (VLDL) output and a suppression of serum triglyceride (as VLDL) levels. Our studies have shown that PUFA suppress hepatic de novo lipogenesis by inhibiting the transcription of genes encoding key enzymes involved in both lipogenesis and glycolysis. Using two models, i.e. the hepatic S14 gene (lipogenic gene model) and L-pyruvate kinase (glycolytic gene model), we have shown that the molecular targets for PUFA action are cis- regulatory elements (PUFA-RE) located within the proximal promoters of these genes. PUFA-RE serve as targets for PUFA-regulated factors (PUFA- RF) that interfere with the hormonal [triiodothyronine (T3) and insulin] activation of gene transcription, i.e. dominant negative control. The following studies are proposed to characterize further the molecular basis of PUFA action: 1) to use a transfection approach of primal hepatocytes to define the DNA sequences that are sufficient and necessary for PUFA-mediated suppression of the S14 gene; 2) to use a transfection approach to understand how PUFA-RE function within the context of the proximal promoter elements and upstream hormone-regulated enhancers; and 3) to isolate and characterize PUFA-RF to define further the mechanism of PUFA-mediated interference of hormone regulation of gene transcription. The information gained from these studies will be of significant biomedical importance because of the elucidation of the molecular mechanisms of PUFA-mediated control of lipogenic gene transcription. These studies may be useful in the development of novel hypolipemic and anti-obesity agents. Finally, we will obtain new insight into PUFA effects on human health and development and how fatty acid effects on hormonal regulation may contribute to the progression of such diseases as obesity, insulin resistance, cardiovascular disease and carcinogenesis.
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