The DOI matches its Crossref record; 50 of the 51 references it cites were found in a registry or an index.
DAGLβ inhibition perturbs a lipid network involved in macrophage inflammatory responses
Open accessAbstract
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.
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“Importantly, DAGL-β inhibition also blocks the LPS-induced production of proinflammatory mediators (Hsu et al, 2012).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Hsu et al, 2012
In the citing paper
“Specifically, DAGL-β is highly expressed in macrophages, and its blockade leads to reduced levels of 2-AG, arachidonic acid, and a variety of proinflammatory arachidonic acid metabolites and proinflammatory cytokines in these cells (Hsu et al, 2012).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Hsu et al, 2012
In the citing paper
“The observation that selective inhibition of DAGL-β, the biosynthetic enzyme expressed predominantly on macrophages and microglia, reduces pro-inflammatory mediators (Hsu et al, 2012), and reverses nociceptive behavior in a mouse model of CCI (Wilkerson et al, 2016a) appears to be at odds with the antinociceptive effects of MAGL inhibitors in this same model.”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Hsu et al, 2012
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Isolation and Structure of a Brain Constituent That Binds to the Cannabinoid Receptor
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2-Arachidonoylgylcerol: A Possible Endogenous Cannabinoid Receptor Ligand in Brain
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Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides
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Self-citationTumor Necrosis Factor-α Signaling in Macrophages
Parameswaran, N., & Patial, S. (2010) · Critical Reviews in Eukaryotic Gene Expression · doi:10.1615/critreveukargeneexpr.v20.i2.10 · Cited by 1,490
Brain monoglyceride lipase participating in endocannabinoid inactivation
Dinh, T. P., Carpenter, D., Leslie, F. M., Freund, T. F., Katona, I., Sensi, S. L., Kathuria, S., & Piomelli, D. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.152334899 · Cited by 1,373
Modulation of anxiety through blockade of anandamide hydrolysis
Kathuria, S., Gaetani, S., Fegley, D., Valiño, F., Duranti, A., Tontini, A., Mor, M., Tarzia, G., Rana, G. L., Calignano, A., et al. (2003) · Nature Medicine · doi:10.1038/nm803 · Cited by 1,293
Activity-Based Protein Profiling: From Enzyme Chemistry to Proteomic Chemistry
Cravatt, B. F., Wright, A. T., & Kozarich, J. W. (2008) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.75.101304.124125 · Cited by 1,270 · cited 3×
“24), whereas neither compound affected basal TNF-α secretion (Supplementary Fig.”
InfluentialSelf-citationA Comprehensive Profile of Brain Enzymes that Hydrolyze the Endocannabinoid 2-Arachidonoylglycerol
Blankman, J. L., Simon, G. M., & Cravatt, B. F. (2007) · Chemistry & Biology · doi:10.1016/j.chembiol.2007.11.006 · Cited by 1,177 · cited 1×
“KT195, for instance, should prove useful not only as a control probe, but also as a pharmacological tool to study ABHD6, which may function as an alternative endocannabinoid hydrolase 9,50 .”
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Pacher, P., & Kunos, G. (2013) · FEBS Journal · doi:10.1111/febs.12260 · Cited by 418
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Metadata
- Authors
- Hsu, K.-L., Tsuboi, K., Adibekian, A., Pugh, H., Masuda, K., & Cravatt, B. F.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Cravatt, Benjamin F
- Venue
- Nature Chemical Biology
- Published
- 2012-10-28
- Volume
- 8
- Issue
- 12
- Pages
- 999-1007
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC3513945
- OpenAlex
- W2134450626
- Cited by
- 222
- References
- 51
- Citations by year
- 2026: 14 · 2025: 7 · 2024: 11 · 2023: 17 · 2022: 17 · 2021: 22 · 2020: 13 · 2019: 15 · 2018: 17 · 2017: 15 · 2016: 22 · 2015: 18 · 2014: 18 · 2013: 15 · 2012: 1
- FWCI
- 12.45
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (U54MH084512, MH-084512)
- National Institute on Drug Abuse (DA033760, P01DA009789, R01DA033760, DA 009789)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- diacylglycerol lipase, 2-arachidonoylglycerol, endocannabinoid system, activity-based probes, macrophage inflammation, eicosanoids, arachidonic acid, cytosolic phospholipase A2, lipopolysaccharide, TNF-α, lipid metabolism, ABHD6
- MeSH terms
- Animals, Arachidonic Acids, Cell Line, Glycerides, Inflammation, Lipoprotein Lipase, Neurons, Prostaglandins, Triazoles, Tumor Necrosis Factor-alpha, Signal Transduction, Cytokines, Arachidonic Acid, Macrophages, Peritoneal, Mice, Knockout, Protein Isoforms, Proteome, Quantitative Structure-Activity Relationship, Lipid Metabolism, Mice, Drug Discovery, Endocannabinoids
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