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المؤلفAllaire, Manon
المؤلفAl Sayegh, Rola
المؤلفMabire, Morgane
المؤلفHammoutene, Adel
المؤلفSiebert, Matthieu
المؤلفCaër, Charles
المؤلفCadoux, Mathilde
المؤلفWan, JingHong
المؤلفHabib, Aida
المؤلفLe Gall, Maude
المؤلفde la Grange, Pierre
المؤلفGuillou, Hervé
المؤلفPostic, Catherine
المؤلفParadis, Valérie
المؤلفLotersztajn, Sophie
المؤلفGilgenkrantz, Hélène
تاريخ الإتاحة2023-11-19T05:45:32Z
تاريخ النشر2023
اسم المنشورJHEP Reports
المصدرScopus
الرقم المعياري الدولي للكتاب25895559
معرّف المصادر الموحدhttp://dx.doi.org/10.1016/j.jhepr.2023.100794
معرّف المصادر الموحدhttp://hdl.handle.net/10576/49409
الملخصBackground & 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.
راعي المشروعThe authors thank V. Fauveau, Institut Cochin, for help in surgery experiments; Olivier Thibaudeau of the Plateau de Morphologie Facility (INSERM UMR 1152, France) and Nicolas Sorhaindo of the Plateforme de Biochimie (CRI, INSERM UMR1149) for their help in the histology and liver function tests; and K. Bailly from the cytometry platform of Cochin Institute and H. Fohrer-Ting from the Centre de Recherche des Cordeliers, Paris University, for cell sorting analyses.
اللغةen
الناشرElsevier
الموضوعInjury
MAGL
Proliferation
Wound healing
العنوانMonoacylglycerol lipase reprograms hepatocytes and macrophages to promote liver regeneration
النوعArticle
رقم العدد8
رقم المجلد5


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