DAGL-Beta Functions as a PUFA-Specific Triacylglycerol Lipase in Macrophages

Here, we apply chemical proteomics and untargeted lipidomics to assign a novel polyunsaturated fatty acid (PUFA)-specific triacylglycerol (TAG) lipase activity for diacylglycerol lipase-beta (DAGLβ) in macrophages. We demonstrate that DAGLβ but not DAGLα is expressed and active in bone marrow-derived macrophages (BMDMs) as determined by DAGL-directed activity-based protein profiling (ABPP). Genetic disruption of DAGLβ resulted in accumulation of cellular TAGs composed of PUFA but not saturated/low unsaturated FA counterparts, which is recapitulated in wild-type macrophages treated with a DAGLβ-selective inhibitor. Biochemical assays with synthetic substrates confirm PUFA-TAGs as authentic DAGLβ substrates. In summary, our findings identify DAGLβ as a PUFA-specific TAG lipase in primary macrophages.