The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis.
The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis.
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DOI：
10.1016/j.jhep.2016.01.035
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发表时间：
2016-06
影响因子：
25.7
通讯作者：
Szabo G
中科院分区：
文献类型：
--
作者：
Bala S;Csak T;Saha B;Zatsiorsky J;Kodys K;Catalano D;Satishchandran A;Szabo G
酒精性肝病（ALD）的范围从脂肪肝到炎症和肝硬化。miRNA-155是炎症的重要调节因子。在这项研究中，我们描述了miR-155在ALD中的体内作用。野生型、WT（C57/BL 6 J）或miR-155 KO和TLR 4 KO小鼠接受Lieber-DeCarli饮食5周。一些小鼠接受玉米油或四氯化碳2或9周。我们发现miR-155 KO小鼠受到保护，免受酒精诱导的脂肪变性和炎症。miR-155 KO小鼠中酒精诱导的脂肪蓄积减少与PPRE和PPARα（miR-155靶标）结合增加和MCP 1产生减少相关。用miR-155抑制剂处理增加了原始和酒精处理的RAW巨噬细胞中的PPARγ表达。在WT小鼠中，酒精增加了脂质代谢基因（FABP 4、LXRα、ACC 1和LDLR），而在KO小鼠中，这一点得到了预防。在miR-155 KO小鼠中，阻止了WT中酒精饮食诱导的CD 163 + CD 206+浸润巨噬细胞和中性粒细胞数量的增加。当暴露于M1极化信号时，从miR-155 KO小鼠分离的Kupffer细胞表现出M2表型的优势，这是由于C/EBPβ增加。酒精饮食或CCl 4处理后，miR-155 KO小鼠中的促纤维化基因减弱。与WT相比，在KO小鼠中观察到CCl 4诱导的羟脯氨酸和α SMA衰减。最后，我们显示TLR 4信号调节miR-155，因为TLR 4 KO小鼠在酒精饮食后没有显示miR-155的诱导。总的来说，我们的结果证明了miR-155在体内酒精诱导的脂肪性肝炎和纤维化中的作用。
Alcoholic liver disease (ALD) ranges from fatty liver to inflammation and cirrhosis. miRNA-155 is an important regulator of inflammation. In this study, we describe the in vivo role of miR-155 in ALD. Wild type, WT (C57/BL6J) or miR-155 KO and TLR4 KO mice received Lieber-DeCarli diet for 5 weeks. Some mice received corn oil or CCl4 for 2 or 9 weeks. We found that miR-155 KO mice are protected from alcohol-induced steatosis and inflammation. The reduction in alcohol-induced fat accumulation in miR-155 KO mice was associated with increased PPRE and PPARα (miR-155 target) binding and decreased MCP1 production. Treatment with a miR-155 inhibitor increased PPARγ expression in naive and alcohol treated RAW macrophages. Alcohol increased lipid metabolism genes (FABP4, LXRα, ACC1 and LDLR) in WT mice and this was prevented in KO mice. Alcohol diet induced increase in the number of CD163+CD206+ infiltrating macrophages and neutrophils in WT was prevented in miR-155 KO mice. Kupffer cells isolated from miR-155 KO mice exhibited predominance of M2 phenotype when exposed to M1 polarized signals and this was due to increased C/EBPβ. Profibrotic genes were attenuated in miR-155 KO mice after alcohol diet or CCl4 treatment. Compared to WT attenuation in CCl4 induced hydroxyproline and α SMA was observed in KO mice. Finally, we show TLR4 signaling regulates miR-155 as TLR4 KO mice showed no induction of miR-155 after alcohol diet. Collectively our results demonstrated the role of miR-155 in alcohol-induced steatohepatitis and fibrosis in vivo.