Abstract

Obesity has become a worldwide phenomenon and has been accompanied by a parallel rise in the incidence of insulin resistance, type 2 diabetes, inflammation, dyslipidemia and cardiovascular disease. Together, these symptoms have been collectively referred to as “cardiometabolic disease" (CMD). Delta-6-desaturase catalyzes the rate limiting step in the conversion of linoleic acid (LA) into arachidonic acid (AA), which in turn is converted into pro-inflammatory eicosanoids. Increasing evidence suggests a link between D6D hyperactivity and the development of CMD, though this hypothesis remains to be tested experimentally. We hypothesized that obesity and a high-fat diet, leading to the development of CMD, will be reversed/prevented by the pharmacological inhibition of D6D using the drug SC-26196. In mouse models of obesity resulting from leptin-deficiency (ob/ob) or a high-fat diet (in LDL receptor knockout mice) a detailed assessment of the acyl composition of serum and hepatic phospholipids was conducted to provide insight into the nature of phospholipid remodeling in disease and with D6D inhibition, as well as the potential interaction of D6D with phosphatidylethanolamine N-methyltransferase (PEMT), the enzyme which catalyzes the hepatic conversion of phosphatidylethanolamine (PE) into phosphatidylcholine (PC). The hepatic PC/PE ratio was used as a surrogate measure for PEMT activity. The extent of CMD was assessed by analyses of serum triglycerides, cholesterol, and macrophage chemoattractant protein-1, as well as hepatic free AA and eicosanoids. Obesity and a high-fat diet resulted in elevated D6D activity, accompanied by manifestations of CMD, which were reversed with D6D inhibition. Though the mechanism of the interaction between D6D and PEMT remains unclear, the results suggest that it may be bidirectional, where D6D may influence PEMT activity, in addition to the reported effects of PEMT on D6D. Differences were observed between the ob/ob and LDLR-/- models in disease etiology, pathophysiology, and response to treatment. These differences should be considered when selecting a research model of CMD. In conclusion, the production of AA through D6D metabolism and the potential involvement of PEMT and other enzymes, such as PLA-2, appear to play an important role in the pathogenesis of CMD by complex interactions with multiple systems that merit further investigation.

Department

Chemistry Department

Degree Name

MS in Chemistry

Graduation Date

2-1-2013

Submission Date

January 2013

First Advisor

Azzazy, Hassan

Second Advisor

Chicco, Adam

Committee Member 1

Ragai, Jehane

Committee Member 2

Madkour, Tarek

Extent

125 p.

Document Type

Master's Thesis

Library of Congress Subject Heading 1

Fatty acids.

Library of Congress Subject Heading 2

Heart -- Diseases.

Rights

The author retains all rights with regard to copyright. The author certifies that written permission from the owner(s) of third-party copyrighted matter included in the thesis, dissertation, paper, or record of study has been obtained. The author further certifies that IRB approval has been obtained for this thesis, or that IRB approval is not necessary for this thesis. Insofar as this thesis, dissertation, paper, or record of study is an educational record as defined in the Family Educational Rights and Privacy Act (FERPA) (20 USC 1232g), the author has granted consent to disclosure of it to anyone who requests a copy.

Institutional Review Board (IRB) Approval

Not necessary for this item

Comments

I would like to thank my advisor and mentor Dr. Hassan Azzazy for his continuous support, for creating exciting opportunities and new learning experiences throughout the three years of my study, and without whom none of this would have been possible. I would also like to thank my co-advisor Dr. Adam Chicco for allowing me to conduct my thesis research at his laboratory at Colorado State University, and for being a patient, supportive and attentive mentor. I thank the Chicco research group at Colorado State University, mely, PhD students Christopher Mulligan, Catherine Le and MS graduate Melissa Routh for their assistance and for making my stay a pleasant one. I thank my colleagues at the American University in Cairo, especially MS graduates Ayaat Mohamed, Mai Mansour and Nouran Ashraf for their advice and assistance. I also thank colleague Maha Gabr at Ain Shams University, Faculty of Medicine, for her support and assistance. I thank the Chemistry Department and the American University in Cairo for their fincial and academic support.

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