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AuthorAllaire, Manon
AuthorAl Sayegh, Rola
AuthorMabire, Morgane
AuthorHammoutene, Adel
AuthorSiebert, Matthieu
AuthorCaër, Charles
AuthorCadoux, Mathilde
AuthorWan, JingHong
AuthorHabib, Aida
AuthorLe Gall, Maude
Authorde la Grange, Pierre
AuthorGuillou, Hervé
AuthorPostic, Catherine
AuthorParadis, Valérie
AuthorLotersztajn, Sophie
AuthorGilgenkrantz, Hélène
Available date2023-11-19T05:45:32Z
Publication Date2023
Publication NameJHEP Reports
ResourceScopus
ISSN25895559
URIhttp://dx.doi.org/10.1016/j.jhepr.2023.100794
URIhttp://hdl.handle.net/10576/49409
AbstractBackground & 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.
SponsorThe 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.
Languageen
PublisherElsevier
SubjectInjury
MAGL
Proliferation
Wound healing
TitleMonoacylglycerol lipase reprograms hepatocytes and macrophages to promote liver regeneration
TypeArticle
Issue Number8
Volume Number5
dc.accessType Open Access


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