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DAGLβ inhibition perturbs a lipid network involved in macrophage inflammatory responses

Academic Article
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Overview

authors

  • Hsu, K. L.
  • Tsuboi, K.
  • Adibekian, Alexander
  • Pugh, H.
  • Masuda, K.
  • Cravatt, Benjamin

publication date

  • December 2012

journal

  • Nature Chemical Biology  Journal

abstract

  • The endocannabinoid 2-arachidonoylglycerol (2-AG) is biosynthesized by diacylglycerol lipases DAGLα and DAGLβ. Chemical probes to perturb DAGLs are needed to characterize endocannabinoid function in biological processes. Here we report a series of 1,2,3-triazole urea inhibitors, along with paired negative-control and activity-based probes, for the functional analysis of DAGLβ in living systems. Optimized inhibitors showed high selectivity for DAGLβ over other serine hydrolases, including DAGLα (∼60-fold selectivity), and the limited off-targets, such as ABHD6, were also inhibited by the negative-control probe. Using these agents and Daglb(-/-) mice, we show that DAGLβ inactivation lowers 2-AG, as well as arachidonic acid and eicosanoids, in mouse peritoneal macrophages in a manner that is distinct and complementary to disruption of cytosolic phospholipase-A2. We observed a corresponding reduction in lipopolysaccharide-induced tumor necrosis factor-α release. These findings indicate that DAGLβ is a key metabolic hub within a lipid network that regulates proinflammatory responses in macrophages.

subject areas

  • Animals
  • Arachidonic Acid
  • Arachidonic Acids
  • Cell Line
  • Cytokines
  • Drug Discovery
  • Endocannabinoids
  • Glycerides
  • Inflammation
  • Lipid Metabolism
  • Lipoprotein Lipase
  • Macrophages, Peritoneal
  • Mice
  • Mice, Knockout
  • Neurons
  • Prostaglandins
  • Protein Isoforms
  • Proteome
  • Quantitative Structure-Activity Relationship
  • Signal Transduction
  • Triazoles
  • Tumor Necrosis Factor-alpha
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Identity

PubMed Central ID

  • PMC3513945

International Standard Serial Number (ISSN)

  • 1552-4450

Digital Object Identifier (DOI)

  • 10.1038/nchembio.1105

PubMed ID

  • 23103940
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Additional Document Info

start page

  • 999

end page

  • 1007

volume

  • 8

issue

  • 12

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