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Department of
Biochemistry
 Lisa
M. Salati, Ph.D.
Ph.D. - University of Minnesota (1986)
Postdoctoral Fellowship - Case Western Reserve University
and the University of Iowa;
Mentor: Alan G. Goodridge
Professor & Vice Chair
Department of Biochemistry
West Virginia University
Robert C. Byrd Health Sciences Center
P.O. Box 9142
Morgantown, WV 26506
Phone: (304) 293-7759
Fax: (304) 293-6846
Email:
lsalati@hsc.wvu.edu
Research:
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:
-
 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 and ultimately regulate the amounts of
the enzymes that synthesize fat (see Fig. 1). 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.
-
 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 and in particular
arachidonic acid 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 that contains
both an enhancer element (ESE) and an inhibitory or silencing
element (ESS). We have further identified candidate splicing
regulatory proteins involved in the nutritional regulation of mRNA
splicing (see Fig. 2). SR proteins bind to the ESE an increase
the rate of splicing; while hnRNPs L, K and A2/B1 bind the ESS and
inhibit splicing. Our ultimate goal is to determine the
mechanisms by which the activities of these proteins are altered by
dietary components.
Research Support
This research has been supported by the National Institutes of Health,
the American Heart Association, and the American Cancer Society
Selected Publications:
- 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.
- 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.
- 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.
- 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.
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