Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Grabner, GF; Eichmann, TO; Wagner, B; Gao, Y; Farzi, A; Taschler, U; Radner, FP; Schweiger, M; Lass, A; Holzer, P; Zinser, E; Tschöp, MH; Yi, CX; Zimmermann, R.
Deletion of Monoglyceride Lipase in Astrocytes Attenuates Lipopolysaccharide-induced Neuroinflammation.
J Biol Chem. 2016; 291(2):913-23
Doi: 10.1074/jbc.M115.683615
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- Führende Autor*innen der Med Uni Graz
- Grabner Gernot
- Co-Autor*innen der Med Uni Graz
- Eichmann Thomas
- Farzi Aitak
- Holzer Peter
- Taschler Ulrike
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- Abstract:
- Monoglyceride lipase (MGL) is required for efficient hydrolysis of the endocannabinoid 2-arachidonoylglyerol (2-AG) in the brain generating arachidonic acid (AA) and glycerol. This metabolic function makes MGL an interesting target for the treatment of neuroinflammation, since 2-AG exhibits anti-inflammatory properties and AA is a precursor for pro-inflammatory prostaglandins. Astrocytes are an important source of AA and 2-AG, and highly express MGL. In the present study, we dissected the distinct contribution of MGL in astrocytes on brain 2-AG and AA metabolism by generating a mouse model with genetic deletion of MGL specifically in astrocytes (MKO(GFAP)). MKO(GFAP) mice exhibit moderately increased 2-AG and reduced AA levels in brain. Minor accumulation of 2-AG in the brain of MKO(GFAP) mice does not cause cannabinoid receptor desensitization as previously observed in mice globally lacking MGL. Importantly, MKO(GFAP) mice exhibit reduced brain prostaglandin E2 and pro-inflammatory cytokine levels upon peripheral lipopolysaccharide (LPS) administration. These observations indicate that MGL-mediated degradation of 2-AG in astrocytes provides AA for prostaglandin synthesis promoting LPS-induced neuroinflammation. The beneficial effect of astrocyte-specific MGL-deficiency is not fully abrogated by the inverse cannabinoid receptor 1 agonist SR141716 (Rimonabant) suggesting that the anti-inflammatory effects are rather caused by reduced prostaglandin synthesis than by activation of cannabinoid receptors. In conclusion, our data demonstrate that MGL in astrocytes is an important regulator of 2-AG levels, AA availability, and neuroinflammation.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals - administration & dosage
- Arachidonic Acids - metabolism
- Astrocytes - enzymology, pathology
- Behavior, Animal - administration & dosage
- Brain - enzymology
- Cytokines - metabolism
- Endocannabinoids - metabolism
- Female - administration & dosage
- Gene Deletion - administration & dosage
- Glial Fibrillary Acidic Protein - metabolism
- Glycerides - metabolism
- Inflammation - enzymology, pathology
- Lipopolysaccharides - administration & dosage
- Mice, Inbred C57BL - administration & dosage
- Mice, Knockout - administration & dosage
- Microglia - metabolism, pathology
- Monoacylglycerol Lipases - metabolism
- Nervous System - enzymology, pathology
- Organ Specificity - administration & dosage
- Receptor, Cannabinoid, CB1 - metabolism