Monoacylglycerol lipase controls endocannabinoid and eicosanoid signaling and hepatic injury in mice.
Monoacylglycerol lipase controls endocannabinoid and eicosanoid signaling and hepatic injury in mice.
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DOI：
10.1053/j.gastro.2012.12.028
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发表时间：
2013-04
期刊：
影响因子：
29.4
通讯作者：
Pacher P
中科院分区：
文献类型：
--
作者：
Cao Z;Mulvihill MM;Mukhopadhyay P;Xu H;Erdélyi K;Hao E;Holovac E;Haskó G;Cravatt BF;Nomura DK;Pacher P
内源性大麻素和花生酸类脂质信号通路在炎症综合征中具有重要作用。单酰基甘油脂肪酶（MAGL）连接这些途径，水解内源性大麻素2-花生四烯酸甘油，产生花生四烯酸前体库前列腺素的生产。我们研究了阻断MAGL是否可以保护肝脏免受炎症和肝脏缺血/再灌注（I/R）和其他损伤。我们分析了给予选择性MAGL抑制剂JZL 184的小鼠、Mgll−/−小鼠、FAAH−/−小鼠以及Cnr 1 −/−和Cnr 2 −/−小鼠中肝脏I/R的影响，这些小鼠的大麻素受体1和2（CB 1/2）受到破坏。收集肝组织并与培养的肝细胞和枯否细胞一起进行沿着分析。我们使用分子生物学、生物化学和质谱分析来测量内源性大麻素、类花生酸以及炎症、氧化应激和细胞死亡的标志物。给予JZL 184的野生型小鼠和Mgll−/−小鼠通过一种机制保护肝脏I/R损伤，该机制涉及通过CB 2增加内源性大麻素信号传导和减少肝脏中类花生酸的产生。JZL 184抑制介导肝I/R损伤的炎症和氧化应激。肝细胞是肝脏MAGL活性和内源性大麻素和花生酸类物质产生的主要来源。JZL 184还保护D-（+）-氨基半乳糖和脂多糖或CCl 4诱导的肝损伤。MAGL通过内源性大麻素和花生酸信号传导促进肝损伤;阻断该途径可保护小鼠免受肝损伤。MAGL抑制剂可能被开发用于治疗使肝脏暴露于氧化应激和炎症损伤的疾病。
The endocannabinoid and eicosanoid lipid signaling pathways have important roles in inflammatory syndromes. Monoacylglycerol lipase (MAGL) links these pathways, hydrolyzing the endocannabinoid 2-arachidonoylglycerol to generate the arachidonic acid precursor pool for prostaglandin production. We investigated whether blocking MAGL protects against inflammation and damage from hepatic ischemia/reperfusion (I/R) and other insults. We analyzed the effects of hepatic I/R in mice given the selective MAGL inhibitor JZL184, in Mgll−/− mice, FAAH−/− mice, and in Cnr1−/− and Cnr2−/− mice, which have disruptions in the cannabinoid receptors 1 and 2 (CB1/2). Liver tissues were collected and analyzed, along with cultured hepatocytes and Kupffer cells. We measured endocannabinoids, eicosanoids, and markers of inflammation, oxidative stress, and cell death using molecular biology, biochemistry, and mass spectrometry analyses. Wild-type mice given JZL184 and Mgll−/− mice were protected from hepatic I/R injury by a mechanism that involved increased endocannabinoid signaling via CB2 and reduced production of eicosanoids in the liver. JZL184 suppressed the inflammation and oxidative stress that mediate hepatic I/R injury. Hepatocytes were the major source of hepatic MAGL activity and endocannabinoid and eicosanoid production. JZL184 also protected from induction of liver injury by D-(+)-galactosamine and lipopolysaccharides or CCl4. MAGL promotes hepatic injury via endocannabinoid and eicosanoid signaling; blockade of this pathway protects mice from liver injury. MAGL inhibitors might be developed to treat for conditions that expose the liver to oxidative stress and inflammatory damage.
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影响因子：
25
作者：
Schlosburg, Joel E.;Blankman, Jacqueline L.;Long, Jonathan Z.;Nomura, Daniel K.;Pan, Bin;Kinsey, Steven G.;Nguyen, Peter T.;Ramesh, Divya;Booker, Lamont;Burston, James J.;Thomas, Elizabeth A.;Selley, Dana E.;Sim-Selley, Laura J.;Liu, Qing-song;Lichtman, Aron H.;Cravatt, Benjamin F.
通讯作者：
Cravatt, Benjamin F.
影响因子：
3.4
作者：
Liu, Wei;Hou, Yufang;Jiang, Ying
通讯作者：
Jiang, Ying
影响因子：
7.3
作者：
Horvath, Bela;Magid, Lital;Pacher, Pal
通讯作者：
Pacher, Pal
影响因子：
29
作者：
Jeong, Won-il;Osei-Hyiaman, Douglas;Kunos, George
通讯作者：
Kunos, George
影响因子：
3.6
作者：
Chanda, Pranab K.;Gao, Ying;Samad, Tarek A.
通讯作者：
Samad, Tarek A.