Targeting arginase-II protects mice from high-fat-diet-induced hepatic steatosis through suppression of macrophage inflammation.
Targeting arginase-II protects mice from high-fat-diet-induced hepatic steatosis through suppression of macrophage inflammation.
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DOI：
10.1038/srep20405
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发表时间：
2016-02-05
影响因子：
4.6
通讯作者：
Ming XF
中科院分区：
文献类型：
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作者：
Liu C;Rajapakse AG;Riedo E;Fellay B;Bernhard MC;Montani JP;Yang Z;Ming XF
非酒精性脂肪性肝病（NAFLD）与肥胖和2型糖尿病相关。低活性的amp活化蛋白激酶（AMPK）、高活性的哺乳动物雷帕霉素靶点（mTOR）信号和巨噬细胞介导的炎症与NAFLD有机制联系。研究精氨酸酶，特别是肝外异构体精氨酸酶ii （Arg-II）在肥胖相关NAFLD中的作用显示出矛盾的结果。本研究表明，与野生型（WT）高脂饲料（HFD）相比，Arg-II - / -小鼠的肝脏脂肪变性、巨噬细胞浸润、TNF-α和IL-6均有所减少。在Arg-II - / -小鼠肝脏中观察到较高的AMPK激活（mTOR信号传导无差异），较低水平的脂肪生成转录因子SREBP-1c和脂肪生成酶的活性/表达。此外，与WT-BMM相比，Arg-II−/−小鼠骨髓源性巨噬细胞（BMM）释放的TNF-α和IL-6减少。与WT-BMM相比，Arg-II−/−-BMM条件培养基促进甘油三酯合成的活性较弱，肝细胞中SREBP-1c和SCD-1的表达较低，AMPK的激活较高。BMM条件培养基的这些作用可以通过中和抗TNF-α和IL-6的抗体来中和。因此，在肥胖中，表达arg - ii的巨噬细胞通过TNF-α和IL-6促进饮食诱导的NAFLD。
Nonalcoholic fatty liver disease (NAFLD) associates with obesity and type 2 diabetes. Hypoactive AMP-activated protein kinase (AMPK), hyperactive mammalian target of rapamycin (mTOR) signaling, and macrophage-mediated inflammation are mechanistically linked to NAFLD. Studies investigating roles of arginase particularly the extrahepatic isoform arginase-II (Arg-II) in obesity-associated NAFLD showed contradictory results. Here we demonstrate that Arg-II−/− mice reveal decreased hepatic steatosis, macrophage infiltration, TNF-α and IL-6 as compared to the wild type (WT) littermates fed high fat diet (HFD). A higher AMPK activation (no difference in mTOR signaling), lower levels of lipogenic transcription factor SREBP-1c and activity/expression of lipogenic enzymes were observed in the Arg-II−/− mice liver. Moreover, release of TNF-α and IL-6 from bone marrow-derived macrophages (BMM) of Arg-II−/− mice is decreased as compared to WT-BMM. Conditioned medium from Arg-II−/−-BMM exhibits weaker activity to facilitate triglyceride synthesis paralleled with lower expression of SREBP-1c and SCD-1 and higher AMPK activation in hepatocytes as compared to that from WT-BMM. These effects of BMM conditioned medium can be neutralized by neutralizing antibodies against TNF-α and IL-6. Thus, Arg-II-expressing macrophages facilitate diet-induced NAFLD through TNF-α and IL-6 in obesity.