Inhibition of monoacylglycerol lipase, an anti-inflammatory and antifibrogenic strategy in the liver
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BMJ Publishing Group
Abstract
Objective Sustained inflammation originating from macrophages is a driving force of fibrosis progression and resolution. Monoacylglycerol lipase (MAGL) is the rate-limiting enzyme in the degradation of monoacylglycerols. It is a proinflammatory enzyme that metabolises 2-arachidonoylglycerol, an endocannabinoid receptor ligand, into arachidonic acid. Here, we investigated the impact of MAGL on inflammation and fibrosis during chronic liver injury. Design C57BL/6J mice and mice with global invalidation of MAGL (MAGL-/-), or myeloid-specific deletion of either MAGL (MAGL Mye-/-), ATG5 (ATG Mye-/-) or CB2 (CB2 Mye-/-), were used. Fibrosis was induced by repeated carbon tetrachloride (CCl 4) injections or bile duct ligation (BDL). Studies were performed on peritoneal or bone marrow-derived macrophages and Kupffer cells. Results MAGL-/-or MAGL Mye-/-mice exposed to CCl 4 or subjected to BDL were more resistant to inflammation and fibrosis than wild-type counterparts. Therapeutic intervention with MJN110, an MAGL inhibitor, reduced hepatic macrophage number and inflammatory gene expression and slowed down fibrosis progression. MAGL inhibitors also accelerated fibrosis regression and increased Ly-6C low macrophage number. Antifibrogenic effects exclusively relied on MAGL inhibition in macrophages, since MJN110 treatment of MAGL Mye-/-BDL mice did not further decrease liver fibrosis. Cultured macrophages exposed to MJN110 or from MAGL Mye-/-mice displayed reduced cytokine secretion. These effects were independent of the cannabinoid receptor 2, as they were preserved in CB2 Mye-/-mice. They relied on macrophage autophagy, since anti-inflammatory and antifibrogenic effects of MJN110 were lost in ATG5 Mye-/-BDL mice, and were associated with increased autophagic flux and autophagosome biosynthesis in macrophages when MAGL was pharmacologically or genetically inhibited. Conclusion MAGL is an immunometabolic target in the liver. MAGL inhibitors may show promising antifibrogenic effects during chronic liver injury. © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.
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Fibrosis, Inflammation, Lipid metabolism, Liver, Macrophages, Animals, Anti-inflammatory agents, Autophagy, Carbamates, Carbon tetrachloride, Cell count, Cells, cultured, Cytokines, Disease progression, Drug evaluation, preclinical, Hydrolases, Inflammation mediators, Liver cirrhosis, experimental, Male, Mice, inbred c57bl, Mice, knockout, Molecular targeted therapy, Monoacylglycerol lipases, Receptor, cannabinoid, cb2, Succinimides, 4 [bis(1,3 benzodioxol 5 yl)hydroxymethyl] 1 piperidinecarboxylic acid 4 nitrophenyl ester, Acylglycerol lipase, Acylglycerol lipase inhibitor, Autophagy related protein 5, Cannabinoid 2 receptor, Cytokine, Lysine, Mjn 110, Unclassified drug, Antiinflammatory agent, Autacoid, Carbamic acid derivative, Hydrolase, Mjn110, Succinimide derivative, Animal cell, Animal experiment, Animal model, Animal tissue, Antifibrotic activity, Antiinflammatory activity, Article, Autophagosome, Bile duct ligation, Bone marrow cell, Bone marrow derived macrophage, C57bl 6 mouse, Chronic liver disease, Controlled study, Cytokine release, Enzyme inhibition, Gene expression, Hepatitis, Kupffer cell, Liver fibrosis, Liver injury, Liver protection, Macrophage culture, Mouse, Nonhuman, Peritoneum macrophage, Priority journal, Remission, Wild type mouse, Animal, C57bl mouse, Cell culture, Disease exacerbation, Drug effect, Enzymology, Experimental liver cirrhosis, Knockout mouse, Macrophage, Metabolism, Molecularly targeted therapy, Pathology, Physiology, Preclinical study, Procedures