目的:Toll样受体4(TLR4)信号通过2种接头蛋白激活:MyD88和含有TIR结构域的接头诱导干扰素-β(TRIF)。TLR4和MyD88在非酒精性脂肪性肝炎(NASH)和纤维化中至关重要。然而,TRIF在TLR4介导的NASH和纤维化中的作用尚不清楚.这项研究调查了TRIF在肝脂肪变性和炎症/纤维化中的不同作用。
方法:将胆碱缺乏的氨基酸定义(CDAA)饮食用于小鼠NASH模型。在这种饮食中,小鼠发展为肝脏脂肪变性,炎症,和纤维化。TLR4野生型和TLR4-/-骨髓嵌合小鼠和TRIF-/-小鼠饲喂CDAA或对照饮食22周。肝脏脂肪变性,炎症,并检查纤维化。
结果:在CDAA饮食诱导的NASH中,与TLR4-/-骨髓小鼠相比,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更高。非酒精性脂肪性肝病活动评分显示,野生型和TLR4-/-骨髓嵌合体均可减少肝脏脂肪变性,两种类型的嵌合体的炎症和肝细胞膨胀水平与全身野生型小鼠相似。值得注意的是,野生型受体比TLR4-/-受体显示更多的肝纤维化。尽管TRIF-/-小鼠显示肝脏脂肪变性减少,这些小鼠表现出更多的肝损伤,炎症,和纤维化比野生型小鼠。TRIF-/-星状细胞和肝细胞在响应脂多糖时产生比野生型细胞更多的C-X-C基序趋化因子配体1(CXCL1)和C-C基序趋化因子配体。始终如一,TRIF-/-小鼠显示CXCL1和CCL3表达增加,同时中性粒细胞和巨噬细胞浸润,促进肝脏炎症和损伤。
结论:在TLR4介导的NASH中,不同的肝细胞在肝脏脂肪变性中具有不同的作用,炎症,和纤维化。TRIF促进肝脏脂肪变性,但抑制损伤,炎症,和纤维化。
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.