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Influence of delta-6-desaturase on hepatic membrane composition in obesity/insulin resistance: implications for the development of cardiometabolic syndrome
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-...
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2013
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| _version_ | 1867613416451997696 |
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| access_status_str | Open Access |
| author | Nemr, Dina Ahmed Safwat |
| author_browse | Nemr, Dina Ahmed Safwat |
| author_facet | Nemr, Dina Ahmed Safwat |
| author_sort | Nemr, Dina Ahmed Safwat |
| collection | Thesis |
| dc_rights_str_mv | 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. |
| description | 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. |
| format | Thesis |
| id | oai:fount.aucegypt.edu:etds-2195 |
| institution | American University in Cairo (Egypt) |
| last_indexed | 2026-06-10T12:35:47.730Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from AUC Knowledge Fountain — bepress |
| publishDate | 2013 |
| publishDateRange | 2013 |
| publishDateSort | 2013 |
| publisher | AUC Knowledge Fountain |
| publisherStr | AUC Knowledge Fountain |
| record_format | dspace |
| source_str | AUC Knowledge Fountain — bepress |
| spelling | oai:fount.aucegypt.edu:etds-2195 Influence of delta-6-desaturase on hepatic membrane composition in obesity/insulin resistance: implications for the development of cardiometabolic syndrome Nemr, Dina Ahmed Safwat 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. 2013-02-01T08:00:00Z thesis application/pdf https://fount.aucegypt.edu/etds/1196 https://fount.aucegypt.edu/context/etds/article/2195/viewcontent/Dina_20Nemr_Thesis_1_22_2013.pdf 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. Theses and Dissertations AUC Knowledge Fountain Insulin resistance Metabolism--Disorders |
| spellingShingle | Insulin resistance Metabolism--Disorders Nemr, Dina Ahmed Safwat Influence of delta-6-desaturase on hepatic membrane composition in obesity/insulin resistance: implications for the development of cardiometabolic syndrome |
| title | Influence of delta-6-desaturase on hepatic membrane composition in obesity/insulin resistance: implications for the development of cardiometabolic syndrome |
| title_full | Influence of delta-6-desaturase on hepatic membrane composition in obesity/insulin resistance: implications for the development of cardiometabolic syndrome |
| title_fullStr | Influence of delta-6-desaturase on hepatic membrane composition in obesity/insulin resistance: implications for the development of cardiometabolic syndrome |
| title_full_unstemmed | Influence of delta-6-desaturase on hepatic membrane composition in obesity/insulin resistance: implications for the development of cardiometabolic syndrome |
| title_short | Influence of delta-6-desaturase on hepatic membrane composition in obesity/insulin resistance: implications for the development of cardiometabolic syndrome |
| title_sort | influence of delta 6 desaturase on hepatic membrane composition in obesity insulin resistance implications for the development of cardiometabolic syndrome |
| topic | Insulin resistance Metabolism--Disorders |
| url | https://fount.aucegypt.edu/etds/1196 https://fount.aucegypt.edu/context/etds/article/2195/viewcontent/Dina_20Nemr_Thesis_1_22_2013.pdf |
| work_keys_str_mv | AT nemrdinaahmedsafwat influenceofdelta6desaturaseonhepaticmembranecompositioninobesityinsulinresistanceimplicationsforthedevelopmentofcardiometabolicsyndrome |