Hsu_2012_Nat.Chem.Biol_8_999

Reference

Title : DAGLbeta inhibition perturbs a lipid network involved in macrophage inflammatory responses - Hsu_2012_Nat.Chem.Biol_8_999
Author(s) : Hsu KL , Tsuboi K , Adibekian A , Pugh H , Masuda K , Cravatt BF
Ref : Nat Chemical Biology , 8 :999 , 2012
Abstract : The endocannabinoid 2-arachidonoylglycerol (2-AG) is biosynthesized by diacylglycerol lipases DAGLalpha and DAGLbeta. 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 DAGLbeta in living systems. Optimized inhibitors showed high selectivity for DAGLbeta over other serine hydrolases, including DAGLalpha ( approximately 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 DAGLbeta 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-alpha release. These findings indicate that DAGLbeta is a key metabolic hub within a lipid network that regulates proinflammatory responses in macrophages.
ESTHER : Hsu_2012_Nat.Chem.Biol_8_999
PubMedSearch : Hsu_2012_Nat.Chem.Biol_8_999
PubMedID: 23103940
Gene_locus related to this paper: human-DAGLA , human-DAGLB

Related information

Gene_locus related to this paper: human-DAGLA , human-DAGLB

Citations formats

Hsu KL, Tsuboi K, Adibekian A, Pugh H, Masuda K, Cravatt BF (2012)
DAGLbeta inhibition perturbs a lipid network involved in macrophage inflammatory responses
Nat Chemical Biology 8 :999

Hsu KL, Tsuboi K, Adibekian A, Pugh H, Masuda K, Cravatt BF (2012)
Nat Chemical Biology 8 :999