抑制单酰甘油脂肪酶，肝脏中的抗炎和抗纤维化策略

StephenW

Inhibition of monoacylglycerol lipase, an anti-inflammatory and antifibrogenic strategy in the liver

    Aida Habib1,2,3, Dina Chokr1,2,4, JingHong Wan1,2, Pushpa Hegde1,2, Morgane Mabire1,2, Matthieu Siebert1,2, Lara Ribeiro-Parenti1,2,5, Maude Le Gall1,2, Philippe Lettéron1,2, Nathalie Pilard1,2, Abdellah Mansouri1,2, Arthur Brouillet6, Matteo Tardelli7, Emmanuel Weiss1,2, Pauline Le Faouder8, Hervé Guillou9, Benjamin F Cravatt10, Richard Moreau1,2, Michael Trauner7, Sophie Lotersztajn1,2
Abstract

Objective Sustained inflammation originating from macrophages is a driving force of fibrosis progression and resolution. Monoacylglycerol lipase (MAGL) is the rate-limiting enzyme in the degradation of monoacylglycerols. It is a proinflammatory enzyme that metabolises 2-arachidonoylglycerol, an endocannabinoid receptor ligand, into arachidonic acid. Here, we investigated the impact of MAGL on inflammation and fibrosis during chronic liver injury.

Design C57BL/6J mice and mice with global invalidation of MAGL (MAGL-/-), or myeloid-specific deletion of either MAGL (MAGLMye-/-), ATG5 (ATGMye-/-) or CB2 (CB2Mye-/-), were used. Fibrosis was induced by repeated carbon tetrachloride (CCl4) injections or bile duct ligation (BDL). Studies were performed on peritoneal or bone marrow-derived macrophages and Kupffer cells.

Results MAGL-/- or MAGLMye-/- mice exposed to CCl4 or subjected to BDL were more resistant to inflammation and fibrosis than wild-type counterparts. Therapeutic intervention with MJN110, an MAGL inhibitor, reduced hepatic macrophage number and inflammatory gene expression and slowed down fibrosis progression. MAGL inhibitors also accelerated fibrosis regression and increased Ly-6Clow macrophage number. Antifibrogenic effects exclusively relied on MAGL inhibition in macrophages, since MJN110 treatment of MAGLMye-/- BDL mice did not further decrease liver fibrosis. Cultured macrophages exposed to MJN110 or from MAGLMye-/- mice displayed reduced cytokine secretion. These effects were independent of the cannabinoid receptor 2, as they were preserved in CB2Mye-/- mice. They relied on macrophage autophagy, since anti-inflammatory and antifibrogenic effects of MJN110 were lost in ATG5Mye-/- BDL mice, and were associated with increased autophagic flux and autophagosome biosynthesis in macrophages when MAGL was pharmacologically or genetically inhibited.

Conclusion MAGL is an immunometabolic target in the liver. MAGL inhibitors may show promising antifibrogenic effects during chronic liver injury.

http://dx.doi.org/10.1136/gutjnl-2018-316137

StephenW

抑制单酰甘油脂肪酶，肝脏中的抗炎和抗纤维化策略

    Aida Habib1,2,3，Dina Chokr1,2,4，JingHong Wan1,2，Pushpa Hegde1,2，Morgane Mabire1,2，Matthieu Siebert1,2，Lara Ribeiro-Parenti1,2,5，Maude Le Gall1,2，Philippe Lettéron1,2，Nathalie Pilard1,2，Abdellah Mansouri1,2，Arthur Brouillet6，Matteo Tardelli7，Emmanuel Weiss1,2，Pauline Le Faouder8，HervéGuillou9，Benjamin F Cravatt10，Richard Moreau1,2，Michael Trauner7，Sophie Lotersztajn1,2
抽象

目的源自巨噬细胞的持续炎症是纤维化进展和消退的驱动力。单酰基甘油脂肪酶（MAGL）是单酰基甘油降解中的限速酶。它是一种促炎酶，将2-花生四烯酰甘油（一种内源性大麻素受体配体）代谢成花生四烯酸。在这里，我们调查了MAGL对慢性肝损伤期间炎症和纤维化的影响。

设计具有MAGL（MAGL - / - ）全局失效或MAGL（MAGLMye - / - ），ATG5（ATGMye - / - ）或CB2（CB2Mye - / - ）的髓样特异性缺失的C57BL / 6J小鼠和小鼠，被使用了。通过重复的四氯化碳（CCl4）注射或胆管结扎（BDL）诱导纤维化。对腹膜或骨髓衍生的巨噬细胞和库普弗细胞进行研究。

结果暴露于CCl4或经历BDL的MAGL - / - 或MAGLMye - / - 小鼠比野生型对应物更耐炎症和纤维化。用MAGL抑制剂MJN110治疗干预可减少肝巨噬细胞数量和炎症基因表达，并减缓纤维化进程。 MAGL抑制剂还加速纤维化消退并增加Ly-6Clow巨噬细胞数量。抗纤维化作用完全依赖于巨噬细胞中的MAGL抑制，因为MJN110治疗MAGLMye - / - BDL小鼠不会进一步降低肝纤维化。暴露于MJN110或来自MAGLMye - / - 小鼠的培养的巨噬细胞显示出减少的细胞因子分泌。这些效应与大麻素受体2无关，因为它们保存在CB2Mye - / - 小鼠中。他们依赖于巨噬细胞自噬，因为MJN110的抗炎和抗纤维化作用在ATG5Mye - / - BDL小鼠中丧失，并且当MAGL在药理学或遗传上被抑制时与巨噬细胞中的自噬通量和自噬体生物合成增加有关。

结论MAGL是肝脏中的免疫代谢靶标。 MAGL抑制剂可能在慢性肝损伤期间显示出有希望的抗纤维化作用。

http://dx.doi.org/10.1136/gutjnl-2018-316137

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StephenW 发表于 2018-10-10 16:04
抑制单酰甘油脂肪酶，肝脏中的抗炎和抗纤维化策略

    Aida Habib1,2,3，Dina Chokr1,2,4，JingHong Wan1, ...

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sky8989

细胞自噬控制着许多重要的生理功能，涉及到细胞部件的降解和回收利用。细胞自噬能快速提供燃料供应能量，或者提供材料来更新细胞部件，因此在细胞面对饥饿和其它种类的应激时，它发挥着不可或缺的作用。在遭受感染之后，细胞自噬能消灭入侵的细胞内细菌活病毒。自噬对胚胎发育和细胞分化也有贡献。细胞还能利用自噬来消灭受损的蛋白质和细胞器，这个质检过程对于抵抗衰老带来的负面影响有举足轻重的意义。遭到扰乱的自噬过程与帕金森氏病、2型糖尿病和老年人体内其他疾病都有所关联。自噬基因的突变可以导致遗传病，自噬机制受到的扰乱还与癌症有关。目前人们正在进行紧张的研究以开发药物，能够在各种疾病中影响自噬机制。
意义。