Cell Chemical Biology
Volume 27, Issue 3, 19 March 2020, Pages 314-321.e5
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Brief Communication
DAGL-Beta Functions as a PUFA-Specific Triacylglycerol Lipase in Macrophages

https://doi.org/10.1016/j.chembiol.2020.01.005Get rights and content
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Highlights

  • Differentiation of SILAC BMDMs for DAGLβ chemoproteomics in primary macrophages

  • Discovery metabolomics to identify PUFA-TAGs as DAGLβ substrates in live BMDMs

  • Biochemical validation that DAGLβ exhibits PUFA-specific TAG lipase activity

Summary

Here, we apply quantitative chemical proteomics and untargeted lipidomics to assign a 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 activity-based protein profiling analysis of SILAC BMDMs. Genetic disruption of DAGLβ resulted in accumulation of cellular TAGs composed of PUFA but not saturated/low unsaturated fatty acid 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.

Keywords

endocannabinoid
2-arachidonoylglycerol
diacylglycerol lipase
inflammation
activity-based protein profiling
chemical proteomics
diacylglycerol
lipidomics
macrophage
triglyceride
lipolysis
TAG lipase
adipose triglyceride

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These authors contributed equally

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