Our lab focuses on understanding the role of sphingolipids in metabolic disease. Sphingolipids are a class of lipid metabolites formed with a serine-based backbone. Many of these are lipid-signaling molecules formed in response to saturated fats, inflammation, or overnutrition. After determining that inhibiting the synthesis of ceramide (the key building block in the generation of all complex sphingolipids) improves insulin resistance and prevents the onset of diabetes in animal models, we have focused on understanding the signals governing ceramide formation and degradation. Modulating these processes can have profound influences on glucose homeostasis, energy homeostasis, cell survival, and cancer biology.
Adiponectin is a protein hormone derived from adipose tissue that exerts protective and regenerative actions on beta cells of the pancreas. We recently discovered that many of adiponectin's beneficial actions can be explained by its ability to break down a potentially toxic metabolite of saturated fat- termed ceramide. The byproduct of this breakdown of ceramide is a building-block for a highly protective signaling lipid termed Sphingosine-1-phosphate (S1P). A class of enzymes termed sphingosine kinases are responsible for generating S1P. The simple 2-step conversion of ceramide to S1P and starkly opposing roles of the two lipids on cell survival and proliferation has prompted the existence of a cellular rheostat governed by these two lipids. We hypothesize that sphingosine kinases and S1P receptors are critically important for cell survival in cell types critically prone to lipid-induced cell death or dysfunction. We are evaluating the role of the ceramide:S1P rheostat in the maintenance of insulin producing cells and important for trophic factors to stimulate the formation of new beta cells in a recovering diabetic pancreas. One of the newly discovered ways of harnessing the protective and healing powers of adiponectin is a growth factor termed FGF21 (fibroblast growth factor 21). FGF21 very rapidly and robustly increases the amount of adiponectin in the bloodstream of rodents and humans.
RheostatShifting sphingolipid metabolism in order to increase S1P and decrease ceramide may critically influence the survival, proliferation, and regeneration of pancreatic b-cells. We are genetically dissecting the components of this rheostat, to evaluate its role in heart disease and diabetes.