Department of Biomedical Sciences

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Publications:

Strommer, L.; Abou El-Ella, G.; Kamel, A.; Marcus, C.;

Hager, P.; Adrian, T. E.; Permert J, 2001 “Upregulation of uncoupling protein homologues in skeletal muscle but not adipose tissue in posttraumatic insulin resistance” J.Biochem

Biophys Res Commun 281,(2),334-40.

Abou El-Ella G, Isaksson B, Permert J, Adrian, T.E.

Increased expression of uncoupling proteins 2 and 3 in insulinresistant muscle from pancreatic cancer patients (submitted to

Journal of Clinical Endocrinology and Metabolism).

Abou EL-Ella G, Adrian TE.

Up-regulation of uncoupling proteins by Tumor necrosis factor-

(TNF-

) and IL-1

in Glut-

4 transfected L6.

(in preparation)

Abou EL-Ella G, Adrian TE.

Modulation of TNF-

-induced expression of uncoupling protein-3 through the sphingomyelinase pathway in myotubes (in preparation)

Oral presentations and Seminars:

Oral presentation at the Midwest Student Biomedical

Research Forum , Omaha NE 2001 “Uncoupling protein 2 and

3 expression in skeletal muscle is significantly increase in posttrumatic rats”

Seminar to the Biomedical Science Dept., Creighton university 2001 “Uncoupling proteins and cachexia”

Oral presentation at the Annual Meeting of the American

Pancreatic Association, Chicago November, 2001 “Marked increase in skeletal muscle uncoupling protein 2 and 3 expression in pancreatic cancer”

Oral presentation at the Midwest student Biomedical research Forum , Omaha NE 2002 “Uncoupling protein 2 and 3 expression in skeletal muscle is markedly increased in pancreatic cancer”

Department of Biomedical Sciences

“Biochemical Studies on Uncoupling

Proteins and Glucose Metabolism in

Skeletal Muscle”

Doctoral Thesis Defense by

Ghada Abou El-Ella

Major Advisor

Dr. Thomas Adrian

Internal Advisor

Dr. Richard F. Murphy

Graduate Committee

Dr. Naser Alsharif

Dr. Terence Lawson

Dr. Alan Richards

Dr. Jack Yee

Friday, December 13, 2002

3 pm

Room B 58

Creighton University

Abstract

Uncoupling protein (UCP) is an inner-mitochondrial membrane protein that uncouples the production of ATP from the electron transport chain, thereby inducing thermogenesis. Recently, a family of UCP homologues was identified, two of which (UCP-2 and UCP-3) are highly

expressed in skeletal muscle. The physiological function of these

UCPs is not established, but evidence suggests that they are involved in the regulation of metabolism rather than thermogenesis.

The aim of my project was to investigate the relationship between uncoupling protein expression and alterations in glucose metabolism in different pathological conditions. In the first part of these studies, the expression of uncoupling proteins in pancreatic cancer patients was determined. A significant increase in UCP-3 and UCP-2 protein and mRNA expression was detected. This increase was associated with impaired insulin response and decreased ATP and phosphocreatine contents, indicating loss of energy. To further explore the relationship between UCP and insulin resistance, expression of the UCPs and glucose metabolism was examined in skeletal muscle samples from a post-traumatic rat model. A significant increase of UCP-2 and

UCP-3 expression was observed, indicating a strong relationship between UCP expression and alterations in glucose metabolism and substrate utilization.

The reported involvement of TNF-

and IL-1

in the pathogenesis of cachexia and insulin resistance triggered investigation of the effect of these inflammatory cytokines on the expression of the UCPs in skeletal muscle cells. TNF-

and IL-1

 induced an increase in the expression of UCP-2 and UCP-3 that was positively associated with an increase in glucose uptake in

Glut-4 transfected L6 myotubes. These findings relate increased glucose uptake to an increase in UCP expression. Finally, the signal pathway through which TNF-

induces its effect was investigated. The results of this study show that TNF-

stimulates an increase in UCP expression and glucose uptake through a

SMase-ceramide-dependant pathway which includes activation of

MAPK and translocation of NF-

B to the nucleus.

Experiments were then designed to try to uncover whether uncoupling caused an increase in glucose uptake or vice versa .

Treatment of Glut-4 transfected L6 myotubes with the uncoupling agent, dinitrophenol resulted in an increase in glucose uptake, which was presumably a response to mitochondrial uncoupling.

The glucose analogue, 2-deoxyglose is taken up into cells and phosphorylated but is not further metabolized. When 80% of the glucose in the media was replaced with 2-deoxyglucose, the stimulatory effect of TNF-

on the UCP expression was abolished, suggesting that the increase in UCP expression is dependent on the increase in glucose uptake. Taken together, these results support our hypothesis that there is a close relationship between an increase in UCP expression and glucose uptake. However, one study shows that glucose uptake increases in response to mitochondrial uncoupling, while the other shows that, when the TNF-

 stimulated increase in glucose uptake is prevented this, in turn, prevents the increase of UCP expression. Thus, a question still remains as to whether increased glucose uptake induces UCP expression or the reverse pertains.

Acknowledgements:

This work was supported by funds from the Egyptian government, the NCI

SPORE program, the Lustgarten Foundation for Pancreatic Cancer

Research and the American Institute for Cancer Research.

Biography:

Born in Assiut Egypt

Bachelors Degree in Veterinary Medical Sciences (BVMSc)

(1991): Assiut University, Egypt – grade: Very Good with Honors.

Masters degree of Veterinary Science (MVSc) in Biochemistry

(1996): Tanta University, Egypt "Effect of Flunixin meglumine

(Finadyne) on carbohydrate metabolism and liver function in female rats"

Position:

Demonstrator, Biochemistry Department, school of Veterinary

Medicine, Tanta University (1992-1996)

Assistant Lecturer, Biochemistry Department, School of

Veterinary Medicine, Tanta University 1996-1997

Assistant Lecturer, Biochemistry Department, School of

Veterinary Medicine, South Valley University 1997-1999

Ph.D. candidate, 1999-present, Department of Biomedical

Sciences, Creighton University

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