Noemi Polgar, Ph.D.
Assistant Professor
Department of Anatomy, Biochemistry & Physiology
Diabetes Research Center
Center for Cardiovascular Research
John A. Burns School of Medicine
651 Ilalo Street, BSB 110
Honolulu, HI 96813
Email: polgar@hawaii.edu
Phone: (808) 692-1422
The Polgar Group is interested in how the exocyst complex contributes to the regulation of facilitative glucose transporter exocytosis in heart muscle cells, and to evaluate the exocyst’s role in cardiac glucose uptake and metabolism in vivo. Dr. Noemi Polgar is one of the Junior Investigators of the NIH-funded Diabetes Research Center of JABSOM , and her primary research focus has been studying the role of the eight-protein exocyst trafficking complex in fuel transporter trafficking in insulin-responsive tissues. Recent studies in adipocytes revealed the important role of the exocyst complex in insulin-induced exocytosis of GLUT4, the predominant glucose transporter in major metabolic tissues. Development of a novel mouse model, with a conditional knockout allele of an exocyst subunit, provides the Group with a unique opportunity to include innovative in vivo analysis of the exocyst’s role in cardiomyocyte glucose transporter trafficking and glucose metabolism under normal and pathological conditions, such as cardiac ischemia.
Insulin resistant cells show defects in insulin-induced exocytosis of the GLUT4 glucose transporter, affecting glucose uptake. The exocyst complex regulates GLUT4 trafficking in response to insulin in cultured adipocytes. However, it is not known if this mechanism is conserved in other, insulin-responsive tissues. Skeletal muscle cells are responsible for the majority of insulin-induced glucose uptake, therefore investigating glucose transporter trafficking in these cells will be key to better understanding the mechanism of glucose homeostasis. Overexpression of Exoc5, a central exocyst subunit can lead to increased exocyst activity, while its knockdown leads to degradation of other subunits. We have recently generated a mouse strain with a conditional Exoc5 allele to analyze exocyst-regulated cellular trafficking in vivo. This unique model enables us to investigate the consequences of Exoc5 inactivation by facilitating generation of tissue-specific conditional Exoc5 knockout animals. We have recently demonstrated that modulation of the exocyst complex can independently regulate GLUT4 exocytosis and glucose uptake in cultured skeletal muscle cells, affecting glucose homeostasis.
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2. Exocyst-mediated Intracellular Trafficking in Cardiac Metabolism
Ischemic heart disease affects over 15 million people in the U.S. Increasing glycolysis in the myocardium is a protective mechanism against ischemic injury. Glucose uptake via glucose transporter GLUT4 is the rate-limiting step of glycolysis in cardiomyocytes. However, the mechanism of glucose transporter delivery to the cardiomyocyte plasma membrane remains poorly understood. Furthermore, molecules that promote this glycolytic shift of energy substrate utilization in cardiac muscle, and thus improve metabolic function during and after ischemia, represent attractive therapeutic targets.
GLUT4 exocytosis to the cardiomyocyte membrane can be triggered by elevated plasma insulin levels or by increased ATP-demand (i.e. during ischemia), via the AMP-activated protein kinase (AMPK). Previous reports suggest that in adipocytes, the exocyst trafficking complex is critical for GLUT4 exocytosis in response to insulin. But it is not known if the insulin-insulin receptor-exocyst-GLUT4 signaling axis is conserved in the cardiomyocytes, or if the exocyst also regulates cardiac glucose uptake via AMPK-induced GLUT4 translocation. We are investigating glucose transporter trafficking in cardiomyocytes to better understand the mechanism of cardiac glucose metabolism under normal and disease conditions.
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3. The Role of the Exocyst Trafficking Complex in Intramuscular Lipid Accumulation and Lipotoxicity
Over 35% of Americans are obese, and the prevalence of obesity-associated disorders like insulin resistance is rising. In obesity, increased free fatty acid (FFA) uptake in skeletal muscle coupled with decreased FFA oxidation results in lipid accumulation, which in turn causes insulin resistance by inhibiting insulin-induced glucose transport. Fatty acid translocase CD36 is responsible for acute FFA uptake in muscle, and CD36 exocytosis can be triggered stimuli, such as insulin release. Yet, we still do not fully understand the mechanisms regulating FFA uptake and lipid accumulation in muscle, and how these pathways promote insulin resistance.
One of the critical regulators of dynamic FFA uptake may be the exocyst trafficking complex. Using our novel cellular and animal model systems, we study the exocyst’s role in muscle FFA uptake, lipid accumulation, and metabolism. Our goal is to elucidate how the exocyst regulates CD36 exocytosis upon stimulus in skeletal muscle cells, and how exocyst inactivation affects FFA uptake and intramuscular lipid accumulation.
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A complete list of Dr. Polgar’s published work can be found below: https://www.ncbi.nlm.nih.gov/sites/myncbi/noemi.polgar.2/bibliography/48707908/public/?sort=date&direction=descending