Regulation of Gene Expression by Dietary Fat

West Virginia University, Morgantown WV

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Abstract

The amount and type of fat in the diet has been the subject of public health recommendations to prevent obesity, diabetes and atherosclerosis. A considerable body of literature has developed that suggests that eating the majority of calories as fat results in the development of insulin resistance and type II diabetes mellitus. Much less is known about how non-pathological fluctuations in dietary fat intake alter intracellular metabolism and how these signaling actions affect events in the nucleus. The glucose-6- phosphate dehydrogenase enzyme provides a unique model to study these nuclear events. First, its role as a lipogenic enzyme makes it important in the etiology of dyslipidemias. Second, it participates in the generation of a putative carbohydrate signaling molecule involved in the transcriptional regulation of both glycolytic and lipogenic genes. Finally, it is reglated at a unique posttranscriptional step permitting the exploration of new regulatory mechanisms beyond transcriptional regulation. We have demonstrated that polyunsaturated fatty acids decrease the rate of splicing of the G6PD pre-mRNA, while transcriptional activity of the gene is not regulated. The overall goal of this project is to understand the molecular mechanism for this regulated splicing. The objective of this application is to define the splicing regulatory proteins involved in this regulation of G6PD splicing and how polyunsaturated fats inhibit their activity. The central hypothesis of the application is that the splicing regulatory region of G6PD exon 12 contains juxtaposed splicing silencing and enhancing elements. The binding of hnRNP K and/or L to the silencer exclude the binding of splicing activators proteins to the enhancer. Polyunsaturated fatty acids regulate the activity of the splicing regulatory proteins by posttranslational modification and/or nuclear abundance. Despite the ubiquitous need for regulated splicing, little is known about the intracellular signals regulating this process. Our experiments are the first to describe inhibition of splicing as a mechanism for inhibition of gene expression by polyunsaturated fat. Thus, the experiments in the current proposal will provide new data on regulation of splicing pre se and define a new pathway by which nutrients regulate gene expression.