(70g) Tracing and Modeling Lipid Homeostasis to Understand Disease.

Metabolism is central to virtually all cellular functions and contributes to diseases like cancer, metabolic syndrome, and neuropathy. My laboratory applies stable isotope tracers, mass spectrometry, and metabolic flux analysis (MFA) to quantify metabolism in cells, animal models, and human patients. We are particularly interested in understanding how amino acid and lipid metabolism are coordinated in the context of cancer, diabetes, and neuropathy. Recent efforts in the lab have aimed to expand MFA frameworks to encompass complex lipid homeostasis, leveraging high-resolution mass spectrometry data and mechanistic networks. A central focus of these studies is the function of serine palmitoyltransferase (SPT) in health and disease. The SPT complex initiates the de novo synthesis of bioactive sphingolipid, integrating amino acid and fatty acid signals into the membrane lipidome. Here I will detail how we apply MFA and to decipher how dysregulation of serine and SPT metabolism contribute to co-morbidities of aging and chronic disease, including neuropathy, macular degeneration, and heart disease. Finally, I will introduce a framework for applying 13C MFA to elucidate lipid synthesis and recycling pathways in cultured cells and precision-cut slice cultures. We validate this method through characterization of lipid biosynthesis and recycling pathways within lung and pancreatic adenocarcinoma tumors. Collectively, these data provide mechanistic insights into the roles of SPT flux and lipid diversity in driving disease states.