Lipid metabolites are well established modulators of inflammation and therefore pharmacological modulation of their biosynthesis and degradation are promising approaches to anti-inflammatory drug treatment.
Many bioactive lipids are derived from polyunsaturated fatty acids (PUFA) and intracellular phospholipase A2 (PLA2) enzymes are considered as being crucial in this process. These enzymes can liberate free arachidonic acid (AA) and other PUFA for metabolization by cyclooxygenase (COX) and lipoxygenase (LOX), leading to synthesis of pro- or anti-inflammatory lipids. Importantly, recent evidence suggests that in specific cell-types, such as astrocytes, AA is provided by monoglyceride lipase (MGL) rather than by PLA2 enzymes. The present project focuses on two enzymes, MGL and alpha/beta hydrolase domain-containing 6 (ABHD6), which both possess monoglyceride (MG) hydrolase activity and have been associated with a number of diseases including cancer, neurodegenerative and metabolic disorders. Based on published data and preliminary experiments, we hypothesize that MG hydrolases play critical roles in lipid signaling pathways in specific cell types by degrading signaling lipids (such as the endocannabinoid 2-arachidonoyl glycerol) and providing ω-3- and ω-6-PUFA for conversion via COX and LOX pathways. The central objective of this project is to generate a comprehensive profile of changes in PUFA metabolites in tissues and cultured cells of mice lacking MGL or ABHD6 under basal conditions and in animal models of disease. In order to translate results from animal studies to human physiology, we will investigate the role of MG hydrolases in the generation and inactivation of lipid signaling molecules in the human placenta. We expect that our work will provide novel insights into the physiological functions of these enzymes and their role in disease.