TRIF Differentially Regulates Hepatic Steatosis and Inflammation/Fibrosis in Mice.
TRIF Differentially Regulates Hepatic Steatosis and Inflammation/Fibrosis in Mice.
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TRIF 差异调节小鼠肝脏脂肪变性和炎症/纤维化
DOI：
10.1016/j.jcmgh.2016.12.004
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发表时间：
2017-05
影响因子：
7.2
通讯作者：
Seki E
中科院分区：
文献类型：
--
作者：
Yang L;Miura K;Zhang B;Matsushita H;Yang YM;Liang S;Song J;Roh YS;Seki E
Toll样受体4(Toll-like Receptor4，TLR4)信号转导通路通过两种接头蛋白激活：MyD88和含有TIR结构域的适配器诱导干扰素-β(TrIF)。TLR4和MyD88在非酒精性脂肪性肝炎(NASH)和肝纤维化中起关键作用。然而，TRIF在TLR4介导的NASH和纤维化中的作用一直难以捉摸。本研究探讨了TRIF在肝脏脂肪变性和炎症/纤维化中的不同作用。胆碱缺乏氨基酸限定(CDAA)饮食用于小鼠NASH模型。在这种饮食中，小鼠会出现肝脏脂肪变性、炎症和纤维化。TLR4野生型和TLR4-/-骨髓嵌合小鼠和TRIF-/-小鼠分别饲喂CDAA或对照饲料22周。检查肝脏脂肪变性、炎症和纤维化。在CDAA饮食诱导的NASH中，野生型骨髓小鼠的丙氨酸氨基转移酶和肝肿瘤坏死因子水平高于TLR4-/骨髓小鼠。非酒精性脂肪性肝病活动评分显示，野生型和TLR4/-骨髓嵌合体都减轻了肝脏脂肪变性，两种类型的嵌合体的炎症水平和肝细胞膨胀程度与全身野生型小鼠相似。值得注意的是，野生型受体比TLR4/-受体表现出更多的肝纤维化。尽管TRIF-/-小鼠的肝脏脂肪变性减轻，但这些小鼠比野生型小鼠表现出更多的肝脏损伤、炎症和纤维化。与野生型细胞相比，Trif-/-星状细胞和肝细胞产生更多的C-X-C基序趋化因子配体1(CXCL1)和C-C基序趋化因子配体。TRIF-/-小鼠表现出CXCL1和CCL3的表达增加，并伴有中性粒细胞和巨噬细胞的浸润，这促进了肝脏的炎症和损伤。在TLR4介导的NASH中，不同的肝细胞在肝脏脂肪变性、炎症和纤维化中起着不同的作用。TRIF促进肝脏脂肪变性，但它抑制损伤、炎症和纤维化。
Toll-like receptor 4 (TLR4) signaling is activated through 2 adaptor proteins: MyD88 and TIR-domain containing adaptor-inducing interferon-β (TRIF). TLR4 and MyD88 are crucial in nonalcoholic steatohepatitis (NASH) and fibrosis. However, the role of TRIF in TLR4-mediated NASH and fibrosis has been elusive. This study investigated the differential roles of TRIF in hepatic steatosis and inflammation/fibrosis. A choline-deficient amino acid defined (CDAA) diet was used for the mouse NASH model. On this diet, the mice develop hepatic steatosis, inflammation, and fibrosis. TLR4 wild-type and TLR4-/- bone marrow chimeric mice and TRIF-/- mice were fed CDAA or a control diet for 22 weeks. Hepatic steatosis, inflammation, and fibrosis were examined. In the CDAA diet–induced NASH, the mice with wild-type bone marrow had higher alanine aminotransferase and hepatic tumor necrosis factor levels than the mice with TLR4-/- bone marrow. The nonalcoholic fatty liver disease activity score showed that both wild-type and TLR4-/- bone marrow chimeras had reduced hepatic steatosis, and that both types of chimeras had similar levels of inflammation and hepatocyte ballooning to whole-body wild-type mice. Notably, wild-type recipients showed more liver fibrosis than TLR4-/- recipients. Although TRIF-/- mice showed reduced hepatic steatosis, these mice showed more liver injury, inflammation, and fibrosis than wild-type mice. TRIF-/- stellate cells and hepatocytes produced more C-X-C motif chemokine ligand 1 (CXCL1) and C-C motif chemokine ligand than wild-type cells in response to lipopolysaccharide. Consistently, TRIF-/- mice showed increased CXCL1 and CCL3 expression along with neutrophil and macrophage infiltration, which promotes liver inflammation and injury. In TLR4-mediated NASH, different liver cells have distinct roles in hepatic steatosis, inflammation, and fibrosis. TRIF promotes hepatic steatosis but it inhibits injury, inflammation, and fibrosis.