Apolipoprotein A5 alleviates LPS/d-GalN-induced fulminant liver failure in mice by inhibiting TLR4-mediated NF-B pathway
Apolipoprotein A5 alleviates LPS/d-GalN-induced fulminant liver failure in mice by inhibiting TLR4-mediated NF-B pathway
复制标题
载脂蛋白 A5 通过抑制 TLR4 介导的 NF-B 通路减轻 LPS/d-GalN 诱导的小鼠暴发性肝衰竭
DOI：
10.1186/s12967-019-1900-9
复制
发表时间：
2019-05-10
影响因子：
7.4
通讯作者：
Chen, En-Qiang
中科院分区：
文献类型：
--
作者：
Tao, Ya-Chao;Wang, Meng-Lan;Chen, En-Qiang
暴发性肝衰竭（FHF）是严重的临床问题，肝移植是主要的治疗手段.但由于供体器官短缺，FHF的总体生存率较低。载脂蛋白A-V（ApoA 5）是甘油三酯代谢的调节剂，据报道可作为术前门静脉栓塞和肝脏手术后残肝生长的预测因子。目的探讨载脂蛋白A5（ApoA 5）对脂多糖/d-氨基半乳糖（LPS/d-GalN）诱导的小鼠暴发性肝衰竭（FHF）的治疗作用。采用实时定量PCR和蛋白质印迹法检测ApoA 5、Toll样受体4（TLR 4）、髓样分化因子88（MyD 88）和核因子κ B p65（NF-Bp 65）的表达。采用全自动生化分析仪测定血清丙氨酸氨基转移酶（ALT）和肿瘤坏死因子-（TNF-α）水平。进行组织学评估和免疫组织化学（IHC）染色。用Kaplan-Meier曲线测定LPS/d-GalN给药后的存活率。同时检测损伤huh 7细胞中ApoA 5的表达。用ApoA 5质粒转染huh 7细胞，用LPS刺激后进行细胞凋亡分析。使用流式细胞术，ApoA 5过表达降低细胞死亡率。ApoA 5不仅能降低血清ALT和TNF-α水平，而且能减轻肝组织HE染色的肝损伤。ApoA 5过表达可抑制TLR 4、MyD 88和NF-Bp 65蛋白表达。但随着LPS浓度的增加，这种抑制作用逐渐减弱。结论ApoA 5通过抑制TLR 4介导的NF-B通路，在一定范围内对LPS/d-GalN诱导的小鼠暴发性肝衰竭具有保护作用。
BackgroundFulminant liver failure (FHF) is a serious clinical problem and liver transplantation is the major intervention. But the overall survival rate of FHF is low owing to the donated organ shortage. Apolipoprotein A-V (ApoA5) is a regulator of triglyceride metabolism and has been reported to act as a predictor for remnant liver growth after preoperative portal vein embolization and liver surgery. This study aimed to investigate the therapeutic effect of ApoA5 on lipopolysaccharide/d-galactosamine (LPS/d-GalN)induced fulminant liver failure in mice.MethodsFHF mouse model was established using LPS/d-GalN and ApoA5 plasmid was injected by tail vein prior to LPS/d-GalN treatment. The expressions of ApoA5, toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor kappa B p65 (NF-Bp65) were assessed by real-time PCR and western blotting. Serum alanine aminotransferase (ALT) and tumor necrosis factor- (TNF-) levels were measured using automatic biochemical analyzer. Histological assessment and immunohistochemical (IHC) staining were conducted. Survival rate after LPS/d-GalN administration was also determined with Kaplan-Meier curve. Meanwhile, the expression of ApoA5 in injured huh7 cells was tested. Cell apoptosis analysis was performed after huh7 cells were transfected with ApoA5 plasmid and stimulated with LPS.ResultsThe expressions of ApoA5 decreased both in injured huh7 cells and FHF mice. ApoA5 overexpression reduced cell death rate using flow cytometry. ApoA5 not only decreased the serum ALT and TNF- levels but also attenuated hepatic damage in hematoxylin-eosin (HE)-stained liver section. The protein expressions of TLR4, MyD88 and NF-Bp65 were inhibited when ApoA5 overexpressed. But the inhibitory effect would weaken with the increasing concentration of LPS in spite of ApoA5 overexpression. Besides, ApoA5 improved liver injury in a dose-dependent manner and the survival rate in FHF mice increased with increasing concentration of ApoA5.ConclusionApoA5 had a protective effect against LPS/d-GalN-induced fulminant liver failure in mice within a certain range by inhibiting TLR4-mediated NF-B pathway.