Monoacylglycerol lipase reprograms hepatocytes and macrophages to promote liver regeneration
Manon Allaire,
Rola Al Sayegh,
Morgane Mabire,
Adel Hammoutene,
Matthieu Siebert,
Charles Caër,
Mathilde Cadoux,
JingHong Wan,
Aida Habib,
Maude Le Gall,
Pierre de la Grange,
Hervé Guillou,
Catherine Postic,
Valérie Paradis,
Sophie Lotersztajn,
Hélène Gilgenkrantz
Affiliations
Manon Allaire
Université de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d’Excellence Inflamex, Paris, France; AP-HP Sorbonne Université, Hôpital Universitaire Pitié Salpêtrière, Service d’Hépato-gastroentérologie, Paris, France
Rola Al Sayegh
Université de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d’Excellence Inflamex, Paris, France
Morgane Mabire
Université de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d’Excellence Inflamex, Paris, France
Adel Hammoutene
Université de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d’Excellence Inflamex, Paris, France; Department of Pathology, Assistance Publique-Hôpitaux de Paris and Université de Paris, Hôpital Beaujon, Clichy, France
Matthieu Siebert
Université de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d’Excellence Inflamex, Paris, France; Surgery Department, Hôpital Bichat-Claude Bernard, APHP, Université de Paris, Paris, France
Charles Caër
Université de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d’Excellence Inflamex, Paris, France
Mathilde Cadoux
Université de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d’Excellence Inflamex, Paris, France
JingHong Wan
Université de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d’Excellence Inflamex, Paris, France
Aida Habib
Department of Basic Medical Sciences, College of Medicine, QU Health Qatar University, Doha, Qatar
Maude Le Gall
Université de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d’Excellence Inflamex, Paris, France
Pierre de la Grange
GenoSplice, Paris, France
Hervé Guillou
Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, PS, Université de Toulouse, Toulouse, France
Catherine Postic
Université de Paris, Institut Cochin, INSERM U1016, CNRS, Paris, France
Valérie Paradis
Université de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d’Excellence Inflamex, Paris, France; Department of Pathology, Assistance Publique-Hôpitaux de Paris and Université de Paris, Hôpital Beaujon, Clichy, France
Sophie Lotersztajn
Université de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d’Excellence Inflamex, Paris, France
Hélène Gilgenkrantz
Université de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d’Excellence Inflamex, Paris, France; Corresponding author. Address: Université de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d’Excellence Inflamex, F-75018 Paris, France. Tel.: +33 157277530.
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 an ubiquitous enzyme at the crossroad between lipid metabolism and inflammation. It converts monoacylglycerols into free fatty acids and metabolises 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. 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 (MAGLHep-/-) or myeloid cells (MAGLMye-/-). Two models of liver regeneration were used: acute toxic carbon tetrachloride injection and two-thirds partial hepatectomy. MAGLMye-/- liver macrophages profiling was analysed by RNA sequencing. A rescue experiment was performed by in vivo administration of interferon receptor antibody in MAGLMye-/- mice. Results: Precision-cut human liver slices 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 in either hepatocytes or myeloid cells displayed delayed liver regeneration. Mechanistically, MAGLHep-/- 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 the type I interferon pathway. Importantly, neutralising the type I interferon pathway restored liver regeneration of MAGLMye-/- mice. Conclusions: Our data demonstrate that MAGL promotes liver regeneration by hepatocyte and macrophage reprogramming. Impact and Implications: 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 in both hepatocytes and macrophages impacts the liver regeneration process, via eicosanoid production by hepatocytes and the modulation of the macrophage interferon pathway profile that restrains hepatocyte proliferation.
