Lisa M. Salati, Ph.D.
	Professor and Vice Chair of Biochemistry Graduate Training: University of Minnesota Fellowship: University of Iowa
	Office: Room 3096A Lab: Room 3096 PO Box 9142 Morgantown, WV 26506	Email: lsalati@hsc.wvu.edu Phone: 304-293-7759 Fax: 304-293-6846

Laboratory Webpage

Research Interests:

Nutrient Control of Cellular Function and Metabolism

Disease applications: Atherosclerosis, diabetes mellitus, metabolic syndrome, obesity

Basic science areas of research: regulation of metabolism, energy homeostasis, hormone action, regulation of gene expression, mRNA processing, protein-nucleic acid interactions, nutritional biochemistry, hepatocyte function

The long-term goal of the laboratory is to understand the molecular details by which fatty acids regulate cellular functions. Currently the laboratory is approaching this from two complementary and ultimately intersecting approaches:

1. Inhibition of insulin signal transduction by fatty acids. Insulin is a major hormonal signal is the intact animal. When humans and other animals consume a diet rich in carbohydrate, blood insulin levels increase and the flux through metabolic pathways favor the storage of excess carbohydrate as glycogen and as the fat, triacylglycerol. The liver is a major site for the conversion of carbohydrate to fat. Flux through this synthetic pathway is decreased when polyunsaturated fat is included in the diet. Our data provides evidence that the decrease in flux is caused by a decrease in insulin signal transduction within the liver. We are defining the pathways by which fatty acids interfere with insulin signal transduction. When the amount of fat in the diet is low the regulation of fat synthesis is reversible but when the amount of fat in the diet increases cellular metabolism is irreversibly altered. It is these latter events that lead to metabolic syndrome. Our goal is to define the steps involved in fatty acid signaling and to distinguish between the normal reversible regulatory mechanisms from the long-term adaptations that occur during obesity and diabetes.

2. Molecular mechanism by which polyunsaturated fats inhibit gene expression. We have chosen to study the mechanism by which fatty acids inhibit gene expression using glucose-6-phosphate dehydrogenase (G6PD) as our model gene. G6PD provides the reducing equivalents for the synthesis of fatty acids and its activity correlates both with the capacity of the liver to synthesize fat and with the amount of circulating blood lipids. My laboratory has discovered a novel mechanism by which polyunsaturated fatty acids can regulate gene expression: decreasing the rate of pre-mRNA splicing. This mechanism accounts most of the regulation of G6PD expression and does so in the absence of changes in G6PD gene transcription. We are analyzing molecular basis for the regulation of mRNA splicing by nutrients. These experiments have defined a splicing regulatory element and identified candidate splicing regulatory proteins involved in the nutritional regulation of mRNA splicing. Our ultimate goal is to determine the mechanisms by which the activities of these proteins are altered by dietary components.

Significance of the research to cardiovascular disease:

For at least three decades, the American public has been encouraged to decrease their consumption of total dietary fat and to increase the ratio of polyunsaturated to saturated fatty acids in the diet. These preventive health recommendations have affected marketing practices within the food industry, affected production by the meat and dairy industry, resulted in new lines of engineered “low fat” foods, and changed the food choices of many individuals. These changes in food intake are based on a correlation between the amount and type of fat consumed, the level of circulating fat in the bloodstream, and the subsequent risk of developing heart disease. A correlation between food consumption and risk of disease is not a cause and effect relationship. In fact, we know little about the actual actions of fat within individual cells in the human body. One phenomenon that suggests polyunsaturated fats may play an important protective role against heart disease is that polyunsaturated fats decrease the ability of the liver to produce additional fatty acids, fatty acids that end up in the bloodstream in the form of VLDL triglyceride.

Research Support:

This research has been supported by the National Institutes of Health, the American Heart Association, and the American Cancer Society

Selected Publications:

1. Salati, L.M., Szeszel-Fedorowicz, W., Tao, H., Gibson, M.A., Amir-Ahmady, B., Stabile, L.P., and Hodge, D.L. (2004) Nutritional regulation of mRNA processing. J. Nutr. 134:2437S-2443S.

2. Talukdar, I, Szeszel-Fedorowicz, W., and Salati, L.M. (2005) Arachidonic acid inhibits the insulin induction of glucose-6-phospohate dehydrogenase via p38 MAP kinase. J. Biol. Chem., 280:40660-40667.

3. Szeszel-Fedorowicz, W., Talukdar, I, Walsh, C.M., and Salati, L.M. (2006) An exonic splicing silencer is involved in the regulated splicing of glucose-6-phosphate dehydrogenase mRNA. J. Biol. Chem., 281:34146-34158.

4. Griffith, B.N., Szeszel-Fedorowicz, W., Walsh, C.M., and Salati, L.M. (2006) Identification of hnRNPs K, L and A2/B1 as candidate proteins involved in the nutritional regulation of mRNA splicing. Biochim. Biophys. A., 1759: 552-561.

    

Lab Personnel:

Travis Cyphert, Graduate Student, Biochemistry and Molecular Biology
Heather Knupp, Graduate Student, Biochemistry and Molecular Biology