Steven D. Clarke, Manabu Nakamura, Jing Xu, and Hye-kyung Cho.
Program of Nutritional Sciences, The University of Texas, Austin, TX, USA.
Early evolutionary success required that the developing organism respond to a myriad of environmental factors. In particular, the organism had to possess an ability to sense periods of nutrient deficiency and excess. Because of this need, the early life forms developed nutrient regulated switches which governed the expression of genes encoding proteins involved in a variety of metabolic functions. As single cell organisms evolved into complex life forms, nutrients continued to regulate protein expression and function at a number of different levels. For example, the binding of a co-factor to an apo-enzyme converts the enzyme into a catalytically active holo-enzyme. The translation rate of a protein (e.g. ferritin) can be determined by the binding of regulatory proteins to stem-loops in the 5’-untranslated region of the transcript. The availability of a nutrient (e.g. iron or selenium) can determine the half-life of an mRNA (e.g. transferrin receptor or glutathione peroxidase). One nutrient which exerts a powerful influence on mRNA synthesis and degradation is dietary fat, particularly (n-6) and (n-3) polyenoic fatty acids (PUFA). Dietary PUFA up-regulate the transcription of genes for fatty acid oxidation and down-regulate transcription of genes involved in lipid synthesis. PUFA also regulate genes that  play pivotal roles in terminal fat cell differentiation, leukotriene degradation and inflammatory response, and monocyte conversion to foam cells. The induction of genes encoding enzymes of lipid oxidation is highly dependent upon the binding of fatty acids to a family of transcription factors called peroxisome proliferator activated receptors (PPARs). Recently, fatty acids were discovered to govern the expression of a second key transcription factor, sterol response element binding protein 1 (SREBP-1). SREBP-1 exists as a 125 kDa membrane anchored precursor which, upon proteolysis releases the mature, transcriptionally active 68 kDA protein. We have found that the ingestion of safflower oil or fish oil reduced the membrane content of precursor SREBP-1 by 60-70%, and this in turn reduced the nuclear content of mature SREBP-1 by 65-85%.  The decrease in SREBP-1 was accompanied by a comparable decrease in the transcription of lipogenic genes. Unlike PUFA, the ingestion of saturated or mono-unsaturated fats had no effect on SREBP-1 expression nor on lipogenic gene expression. Nuclear run-on assays revealed that PUFA suppressed SREBP-1 expression by decreasing the stability of SREBP-1 mRNA. These data indicate that the regulation of gene transcription by dietary fatty acids involves two pivotal transcription factors, PPAR and SREBP-1. In summary, dietary constituents exert a profound and direct impact on the expression of genes involved in a wide array of cellular functions. Identifying these gene targets should provide insight into how nutrients exert both beneficial and detrimental effects on the development of nutritionally related pathophysiologies.