Date of Defense
9-9-2025 1:00 PM
Location
Yannah Theater, Second Floor, Block C (2C010), Male Side, CMHS
Document Type
Dissertation Defense
Degree Name
Doctor of Philosophy in Biomedical Sciences
College
CMHS
Department
Genetics & Genomics
First Advisor
Nadia Akawi
Keywords
Ceramide, Cardiometabolic Disease, LC-MS/MS, Biomarkers, Therapeutic targets, Oxidative Stress, Endothelial Dysfunction, Sodium-Glucose Cotransporter-2 Inhibitors, Sitagliptin.
Abstract
Ceramides (Cer), a subclass of sphingolipids with potent bioactive properties, have gained recognition as key players in the pathogenesis of cardiometabolic diseases (CMD). They modulate critical cellular functions such as apoptosis, inflammation, insulin signaling, and oxidative stress. This dissertation explores the dual role of Cer as both early diagnostic markers and therapeutic targets, bridging clinical insights with mechanistic understanding through a combination of human and experimental studies.
A highly sensitive liquid chromatography–tandem mass spectrometry (LC-MS/MS) method was developed and validated to quantify intracellular levels of specific Cer species, including CerC16:0, CerC18:0, CerC22:0, CerC24:0, and CerC24:1. This method was translated into a clinical setting, enabling the establishment of the first pediatric reference ranges for Cer in a cohort of Emirati youth (n=582). Notably, levels of CerC16:0 and CerC18:0 were positively associated with conventional CMD risk factors, underscoring their potential as early biomarkers—detectable even before the manifestation of traditional indicators.
In order to assess the therapeutic potential of Cer as targeted molecules, we evaluated changes in their profiles in adults with type 2 diabetes, who are undergoing treatment with sodium-glucose cotransporter-2 inhibitors (SGLT2i). The therapy led to marked reduction in circulating high-risk Cer, alongside improvements in oxidative stress and aging-related biomarkers, suggesting that Cer modulation may contribute to the cardiometabolic benefits of SGLT2i therapy.
In vitro and in vivo studies were conducted to further explore the mechanistic underpinnings behind the impacts of Cer. In telomerase-immortalized human aortic endothelial cells (TeloHAECs), short-term exposure to CerC18:0 led to reduced cell viability, elevated oxidative stress, and modifications in endothelial nitric oxide synthase (eNOS) phosphorylation, implicating Cer accumulation in endothelial dysfunction. Another high-fat diet rodent model revealed a reversal of these effects after treatment with Sitagliptin, which lowered plasma levels of high-risk Cer, mitigated oxidative stress, and improved both hepatic steatosis and cardiac function. Restoration of eNOS/AKT signaling in cardiac tissue and structural improvements has validated the therapeutic relevance of targeting Cer pathways. Overall, this work demonstrates that Cer are not only promising biomarkers for early CMD risk detection but also are modifiable targets, paving the way for novel interventions to combat metabolic and vascular complications.
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Genetic Phenomena Commons, Genetic Processes Commons, Genetic Structures Commons, Medical Genetics Commons
THE ROLE OF CERAMIDES AS BIOMARKERS AND THERAPEUTIC TARGETS FOR CARDIOMETABOLIC DISEASE AND ITS INTERSECTION WITH CELLULAR AGING
Yannah Theater, Second Floor, Block C (2C010), Male Side, CMHS
Ceramides (Cer), a subclass of sphingolipids with potent bioactive properties, have gained recognition as key players in the pathogenesis of cardiometabolic diseases (CMD). They modulate critical cellular functions such as apoptosis, inflammation, insulin signaling, and oxidative stress. This dissertation explores the dual role of Cer as both early diagnostic markers and therapeutic targets, bridging clinical insights with mechanistic understanding through a combination of human and experimental studies.
A highly sensitive liquid chromatography–tandem mass spectrometry (LC-MS/MS) method was developed and validated to quantify intracellular levels of specific Cer species, including CerC16:0, CerC18:0, CerC22:0, CerC24:0, and CerC24:1. This method was translated into a clinical setting, enabling the establishment of the first pediatric reference ranges for Cer in a cohort of Emirati youth (n=582). Notably, levels of CerC16:0 and CerC18:0 were positively associated with conventional CMD risk factors, underscoring their potential as early biomarkers—detectable even before the manifestation of traditional indicators.
In order to assess the therapeutic potential of Cer as targeted molecules, we evaluated changes in their profiles in adults with type 2 diabetes, who are undergoing treatment with sodium-glucose cotransporter-2 inhibitors (SGLT2i). The therapy led to marked reduction in circulating high-risk Cer, alongside improvements in oxidative stress and aging-related biomarkers, suggesting that Cer modulation may contribute to the cardiometabolic benefits of SGLT2i therapy.
In vitro and in vivo studies were conducted to further explore the mechanistic underpinnings behind the impacts of Cer. In telomerase-immortalized human aortic endothelial cells (TeloHAECs), short-term exposure to CerC18:0 led to reduced cell viability, elevated oxidative stress, and modifications in endothelial nitric oxide synthase (eNOS) phosphorylation, implicating Cer accumulation in endothelial dysfunction. Another high-fat diet rodent model revealed a reversal of these effects after treatment with Sitagliptin, which lowered plasma levels of high-risk Cer, mitigated oxidative stress, and improved both hepatic steatosis and cardiac function. Restoration of eNOS/AKT signaling in cardiac tissue and structural improvements has validated the therapeutic relevance of targeting Cer pathways. Overall, this work demonstrates that Cer are not only promising biomarkers for early CMD risk detection but also are modifiable targets, paving the way for novel interventions to combat metabolic and vascular complications.