Inhibition of monoacylglycerol lipase, an anti-inflammatory and antifibrogenic strategy in the liver

Abstract

ObjectiveSustained 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.DesignC57BL/6J mice and mice with global invalidation of MAGL (MAGL -/- ), or myeloid-specific deletion of either MAGL (MAGLMye-/-), ATG5 (ATGMye-/-) or CB2 (CB2Mye-/-), were used. Fibrosis was induced by repeated carbon tetrachloride (CCl4) injections or bile duct ligation (BDL). Studies were performed on peritoneal or bone marrow-derived macrophages and Kupffer cells.ResultsMAGL -/- or MAGLMye-/- mice exposed to CCl4 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-6Clow macrophage number. Antifibrogenic effects exclusively relied on MAGL inhibition in macrophages, since MJN110 treatment of MAGLMye-/- BDL mice did not further decrease liver fibrosis. Cultured macrophages exposed to MJN110 or from MAGLMye-/- mice displayed reduced cytokine secretion. These effects were independent of the cannabinoid receptor 2, as they were preserved in CB2Mye-/- mice. They relied on macrophage autophagy, since anti-inflammatory and antifibrogenic effects of MJN110 were lost in ATG5Mye-/- BDL mice, and were associated with increased autophagic flux and autophagosome biosynthesis in macrophages when MAGL was pharmacologically or genetically inhibited.ConclusionMAGL is an immunometabolic target in the liver. MAGL inhibitors may show promising antifibrogenic effects during chronic liver injury.

Inhibition of monoacylglycerol lipase for the treatment of liver disease: tempting but still playing with fire

“…The authors had shown in previous studies that activation of cannabinoid 2 receptors (CB2R), present also on macrophages, displays beneficial anti-inflammatory and antifibrotic effects 5. However, the beneficial effects of MAGL inhibition in their present study were also preserved in mice lacking CB2R on cells of the myeloid lineage 6. In subsequent in vitro and in vivo studies, Habib et al revealed that the anti-inflammatory and antifibrotic effects of MAGL inhibition are mediated via an induction of the autophagic flux and autophagosome biosynthesis in macrophages 6.…”

“…However, the beneficial effects of MAGL inhibition in their present study were also preserved in mice lacking CB2R on cells of the myeloid lineage 6. In subsequent in vitro and in vivo studies, Habib et al revealed that the anti-inflammatory and antifibrotic effects of MAGL inhibition are mediated via an induction of the autophagic flux and autophagosome biosynthesis in macrophages 6. Herewith, this study unravelled a so far unknown mechanism of action of MAGL and suggest MAGL as potential target for the treatment of hepatic inflammation and fibrosis.…”

“…In this issue, Habib et al provide interesting new insights into the impact of MAGL on the development as well as the resolution of hepatic inflammation and fibrosis in different experimental models of chronic liver injury 6. By use of genetic approaches as well as pharmacological MAGL inhibition, they showed that MAGL inhibition diminished hepatic inflammation and fibrosis but accelerated fibrosis resolution.…”

“…AA is the precursor of different prostanoids (prostaglandins, prostacyclins, thromboxanes) and leukotrienes that act as intracellular as well as extracellular signalling molecules and herewith also affect different parenchymal and non-parenchymal liver cells as well as extrahepatic cells. In this issue, Habib et al 6 newly describe an inhibitory effect of MAGL on autophagic flux and autophagosome biosynthesis in macrophages. MAGL’s impact on autophagy in other cells and tissues still needs to be explored.…”

“…In their study, Habib et al focused on mouse models not related to liver steatosis 6. Still, previous studies had already shown that MAGL deficiency prevents high-fat diet-induced insulin resistance 7.…”