Monoacylglycerol lipase reprograms hepatocytes and macrophages to promote liver regeneration
Manon Allaire, Rola Al Sayegh, Morgane Mabire, Adel Hammoutène, Matthieu Siebert, Charles Caër, Mathilde Cadoux, JingHong Wan, Aı̈da Habib, Maude Le Gall, Pierre de la Grange, Hervé Guillou, Catherine Postic, Valérie Paradis, Sophie Lotersztajn, Hélène Gilgenkrantz
Abstract
Background & Aims Liver regeneration is a repair process in which metabolic reprogramming of parenchymal and inflammatory cells plays a major role. Monoacylglycerol lipase (MAGL) is a ubiquitous enzyme at the crossroad between lipid metabolism and inflammation. It converts monoacylglycerols into free fatty acids and metabolizes 2-arachidonoylglycerol into arachidonic acid, being thus the major source of pro-inflammatory prostaglandins in the liver. In this study, we investigated the role of MAGL in liver regeneration. Methods Hepatocyte proliferation was studied in vitro in hepatoma cell lines and ex vivo in precision-cut human liver slices (PCLS). Liver regeneration was investigated in mice treated with a pharmacological MAGL inhibitor, MJN110, as well as in animals globally invalidated for MAGL (MAGL -/- ) and specifically invalidated in hepatocytes (MAGL Hep-/- ) or myeloid cells (MAGL Mye-/- ). Two models of liver regeneration were used: acute toxic CCl 4 injection and two third partial hepatectomy. MAGL Mye-/- liver macrophages profiling was analyzed by RNASequencing. A rescue experiment was performed by in vivo administration of interferon receptor antibody in MAGL Mye-/- mice. Results PCLS from patients with chronic liver disease and human hepatocyte cell lines exposed to MJN110 showed reduced hepatocyte proliferation. Mice with global invalidation or mice treated with MJN110 showed blunted liver regeneration. Moreover, mice with specific deletion of MAGL either in hepatocytes or in myeloid cells displayed delayed liver regeneration. Mechanistically, MAGL Hep-/- mice showed reduced liver eicosanoid production, in particular prostaglandin E2 that negatively impacts on hepatocyte proliferation. MAGL inhibition in macrophages resulted in the induction of type 1 interferon pathway (IFN–I). Importantly, neutralizing the IFN-I pathway restored liver regeneration of MAGL Mye-/- mice. Conclusions Our data demonstrate that MAGL promotes liver regeneration by hepatocyte and macrophage reprogramming. Lay Summary By using human liver samples and mouse models of global or specific cell type invalidation, we show that the monoacylglycerol pathway plays an essential role in liver regeneration. We unveil the mechanisms by which MAGL expressed both in hepatocytes and in macrophages impacts the liver regeneration process, via eicosanoid production by hepatocytes and the modulation of the macrophage interferon pathway profile which restrains hepatocyte proliferation.