Monoacylglycerol lipase reprograms hepatocytes and macrophages to promote liver regeneration

Background & AimsLiver regeneration is a repair process in which metabolic reprogramming of parenchymal and inflammatory cells plays major role. Monoacylglycerol lipase (MAGL) ubiquitous enzyme at the crossroad between lipid metabolism inflammation. It converts monoacylglycerols into free fatty acids metabolizes 2-arachidonoylglycerol arachidonic acid, being thus source pro-inflammatory prostaglandins liver. In this study, we investigated role MAGL liver regeneration.MethodsHepatocyte proliferation was studied vitro hepatoma cell lines ex vivo precision-cut human slices (PCLS). Liver mice treated with pharmacological inhibitor, MJN110, as well animals globally invalidated for (MAGL-/-) specifically hepatocytes (MAGLHep-/-) or myeloid (MAGLMye-/-). Two models were used: acute toxic CCl4 injection two third partial hepatectomy. MAGLMye-/- macrophages profiling analyzed by RNASequencing. A rescue experiment performed administration interferon receptor antibody mice.ResultsPCLS from patients chronic disease hepatocyte exposed to MJN110 showed reduced proliferation. Mice global invalidation blunted regeneration. Moreover, specific deletion either displayed delayed Mechanistically, MAGLHep-/- eicosanoid production, particular prostaglandin E2 that negatively impacts on inhibition resulted induction type 1 pathway (IFN–I). Importantly, neutralizing IFN-I restored mice.ConclusionsOur data demonstrate promotes macrophage reprogramming.Lay SummaryBy using samples mouse invalidation, show monoacylglycerol an essential We unveil mechanisms expressed both process, via production modulation profile restrains