Monoacylglycerol lipase reprograms hepatocytes and macrophages to promote liver regeneration
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 monoacylglycerol...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | JHEP Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589555923001258 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Manon Allaire |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T22:21:33Z |
| format | Article |
| id | doaj.art-346571883a5f4eb1b52cd8a45a9591b1 |
| institution | Directory Open Access Journal |
| issn | 2589-5559 |
| language | English |
| last_indexed | 2024-03-12T22:21:33Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JHEP Reports |
| spelling | doaj.art-346571883a5f4eb1b52cd8a45a9591b12023-07-23T04:56:10ZengElsevierJHEP Reports2589-55592023-08-0158100794Monoacylglycerol lipase reprograms hepatocytes and macrophages to promote liver regenerationManon Allaire0Rola Al Sayegh1Morgane Mabire2Adel Hammoutene3Matthieu Siebert4Charles Caër5Mathilde Cadoux6JingHong Wan7Aida Habib8Maude Le Gall9Pierre de la Grange10Hervé Guillou11Catherine Postic12Valérie Paradis13Sophie Lotersztajn14Hélène Gilgenkrantz15Université 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, FranceUniversité de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d’Excellence Inflamex, Paris, FranceUniversité de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d’Excellence Inflamex, Paris, FranceUniversité 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, FranceUniversité 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, FranceUniversité de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d’Excellence Inflamex, Paris, FranceUniversité de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d’Excellence Inflamex, Paris, FranceUniversité de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d’Excellence Inflamex, Paris, FranceDepartment of Basic Medical Sciences, College of Medicine, QU Health Qatar University, Doha, QatarUniversité de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d’Excellence Inflamex, Paris, FranceGenoSplice, Paris, FranceToxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, PS, Université de Toulouse, Toulouse, FranceUniversité de Paris, Institut Cochin, INSERM U1016, CNRS, Paris, FranceUniversité 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, FranceUniversité de Paris, INSERM, U1149, CNRS, ERL 8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d’Excellence Inflamex, Paris, FranceUniversité 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.http://www.sciencedirect.com/science/article/pii/S2589555923001258Wound healingInjuryMAGLProliferation |
| spellingShingle | 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 Monoacylglycerol lipase reprograms hepatocytes and macrophages to promote liver regeneration JHEP Reports Wound healing Injury MAGL Proliferation |
| title | Monoacylglycerol lipase reprograms hepatocytes and macrophages to promote liver regeneration |
| title_full | Monoacylglycerol lipase reprograms hepatocytes and macrophages to promote liver regeneration |
| title_fullStr | Monoacylglycerol lipase reprograms hepatocytes and macrophages to promote liver regeneration |
| title_full_unstemmed | Monoacylglycerol lipase reprograms hepatocytes and macrophages to promote liver regeneration |
| title_short | Monoacylglycerol lipase reprograms hepatocytes and macrophages to promote liver regeneration |
| title_sort | monoacylglycerol lipase reprograms hepatocytes and macrophages to promote liver regeneration |
| topic | Wound healing Injury MAGL Proliferation |
| url | http://www.sciencedirect.com/science/article/pii/S2589555923001258 |
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