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 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.The 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.Scopu

La localisation tumorale des cancers du côlon droit ne modifie pas la longueur de résection colique : expérience du CHU de Grenoble

Background: Colorectal cancer is increasingly recognized as representing a heterogenous group of tumors: While left segmental colectomy is an accepted and oncologicaly safe practice for left-sided colonic cancer, most authors agree that there is no room for effective segmental resection of right-sided cancer for oncological objectives. Length of the resected colon is an impotant point of debate. To our knowledge, caecum and ascending colon cancer have not been analysed like different groups of tumors. The objective of this study is to see if retrospectively in our center, surgical treatment of caecal cancer would differ with ascending colon cancer. Methods: A retrospective review of all consecutive patients with right colonic resection for cancer admitted to the University hospital of Grenoble from january 2005 to August 2016 was performed. Main outcome of this study was to compare the length of colonic resection, between caecal primary cancer and ascending colonic cancer. Results : Among operated patients, tumor was localised preoperatively on caecum in 110 cases and on the right ascending colon in 119 cases. Preoperative localisation had no effect on the colonic length resected (mean 24.5, 24+/- 10.34 vs 25 +/- 7.281 p= 0.95), on the number of harvested lymph nodes with a mean of 15 (+/-7.6) nodes in the caecal group versus 15.2 (+/-7.3) (p=0.72). We noticed 15 cases of discordance between pre and post operative location (4 vs 11, p=0.08). Conclusion: ln our center, we have not found statistical differences in length resection from tumors located on the caecum or in the ascendant colon.Introduction : Le cancer colorectal est de plus en plus reconnu comme une entité composée de lésions hétérogènes. Alors que la pratique d'une résection colique gauche segmentaire est une pratique acceptée et reconnue, la plupart des auteurs admettent qu'il n'existe pas de place pour une résection colique droite économe pour des raisons oncologiques. La longueur de la pièce de résection colique est toujours un sujet à controverse. A notre connaissance, les cancers du caecum et du côlon ascendant n'ont pas encore été analysés séparément. L'objectif de cette étude est de comparer la longeur de résection colique en fonction de la localisation préopératoire. Matériel et méthode : Etude rétrospective, monocentrique, registre de l'ensemble des patients opérés au CHU de Grenoble entre Janvier 2005 et Août 2016 au CHU de Grenoble d'une colectomie pour cancer du côlon droit. Le critère de jugement principal de cette étude est la longueur de la pièce de résection colique. Résultats : La tumeur était localisée au niveau du caecum dans 110 cas et au niveau du côlon ascendant dans 119. Il n'a pas été mis en évidence de différence significative entre les deux groupes au niveau de la longueur de résection colique (24cm +/-10,34 vs 25 +/-7,28, p=0,95), sur le nombre de ganglions receuillis (15 +/- 7,6 vs 15,2 +/- 7,3; p =0,72). Nous avons identifié 15 cas de discordance entre localisation pré et postopératoire (4 vs 11, p =0,08). Conclusion : Au CHU de Grenoble, nous n'avons pas trouvé de différence de longueur de résection colique entre tumeurs du caecum et du colon ascendant

Similar length of colon is removed regardless of localization in right-sided colonic cancer surgery

International audienceBACKGROUND:Colorectal cancers represent a heterogenous group of tumours. While left segmental colectomy is an accepted and oncologically safe practice for left-sided colonic cancer (CC), some authors suggest that limited segmental resection of right-sided cancer should be debated in order to preserve length of the resected colon. To our knowledge, caecum and ascending CC have not been analysed as different groups of tumours. The objective of this study was to assess if, retrospectively, surgical treatment of caecal cancer differed from ascending CC.METHODS:A review of all consecutive patients with right colonic resection for cancer admitted to the University hospital of Grenoble from January 2005 to August 2016 was performed. Length of resected colon was compared between caecal primary and ascending CC. Other technical and pathological aspects were analysed such as minimal invasive surgery and number of harvested lymph nodes from anatomic specimens.RESULTS:Among operated patients, tumour was localized pre-operatively on caecum in 110 cases and on the right ascending colon in 119 cases. Pre-operative localization had no effect on resected colon length (mean 24.5 cm, 24 ± 10.34 versus 25 cm ± 7.28, P = 0.95), on the number of harvested lymph nodes with a mean of 15 (±7.6) nodes in the caecal group versus 15.2 (±7.3) (P = 0.72). We noticed 15 cases of discordance between pre- and post-operative localization (4 versus 11, P = 0.08).CONCLUSION:Length of resected colon does not differ depending on localization of tumour in our center

Dynamics of molybdenum and barium in the Bay of Brest (France) explained by phytoplankton community structure and aggregation events

International audiencePrimary producers are essential organisms for marine ecosystems because they form the basis of food webs, produce half of atmospheric oxygen and are involved in various biogeochemical cycles. At the end of a bloom event, phytoplankton cells are known to produce organic compounds that act as a ‘cement’, allowing the cells to stick together and form large sinking structures called aggregates. These aggregates are microenvironments with chemical properties that are very different from the surrounding water. The main objective of this study was to determine how the temporal variations in cell assemblages over time and the formation of aggregates following a bloom affect the concentrations of molybdenum (Mo) and barium (Ba) in the water column, which are elements typically measured within accretionary hard tissues (e.g., mollusc shells) to track phytoplankton dynamics in the environment. To do so, we performed an environmental monitoring from March to October 2021 at Lanvéoc in the Bay of Brest (France) during which several biological (e.g., variations in phytoplankton assemblages) and chemical (e.g., chemical properties of the water column) parameters were measured once to twice per week. Our results show that spring and summer blooms of Gymnodinium, known to be enriched in Mo, could be one of the reasons explaining the particulate Mo enrichments in the water column. In addition, large phytoplankton aggregates transported a significant amount of Mo to the seafloor and associated suspension feeders. In contrast, the temporal variations in dissolved and particulate Ba concentration were strongly influenced by the formation of diatom blooms. Interestingly, there was a significant shift in Ba from the dissolved to the particulate fraction during the largest diatom bloom in late spring, associated with a significant Ba transport to the seafloor, which may be explained by the adsorption of this element onto diatom frustules. This study therefore highlights the impacts of phytoplankton on the dynamics of these elements in coastal ecosystems

Proceedings of the annual meeting of the French Society of Astronomy & Astrophysics

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