肝脏X受体激活对α-GalCer诱导的小鼠肝损伤保护机制探讨

Potential Mechanism of Protective Effect of Liver X Receptor Activation on α-GalCer-induced Liver Injury in Mice

背景:肝脏X受体(LXR)属于核受体超家族成员,对脂类代谢相关基因的转录调控起关键作用,同时具有调节免疫反应和抗炎效应。目的:研究LXR激活对α-GalCer诱导的小鼠肝损伤保护作用的可能机制。方法:15只C57BL/6J小鼠随机分为正常对照组、α-GalCer模型组和LXR治疗组,后两组以α-GalCer腹腔注射诱导肝损伤模型,LXR治疗组于造模前连续7 d腹腔注射LXR激动剂T0901317。造模6 h后处死小鼠,行肝组织病理学检查和血清ALT、AST水平检测,免疫组化染色检测肝组织白细胞介素-6(IL-6)表达,蛋白质印迹法检测肝内PI3K/Akt/NF-κB信号通路激活情况,实时RT-PCR检测肝组织肿瘤坏死因子-α(TNF-α)、诱导型一氧化氮合酶(iNOS)mRNA表达。结果:与正常对照组相比,α-GalCer模型组小鼠肝损伤明显,血清转氨酶水平升高,肝组织IL-6、TNF-α、iNOS表达上调,PI3K/Akt/NF-κB信号通路激活。LXR治疗组肝损伤和血清转氨酶水平较α-GalCer模型组显著改善,肝组织炎症介质表达下调,PI3K/Akt/NF-κB信号通路激活受抑。结论:LXR激活可调节免疫反应,抑制肝脏炎症,从而显著减轻α-GalCer诱导的小鼠肝损伤,其机制可能与抑制PI3K/Akt/NF-κB信号通路激活有关。

Liver X receptor （LXR） is a member of nuclear receptors superfamily that plays central role in the transcriptional control of genes involved in lipid metabolism. Meanwhile, LXR also has immune regulatory and antiinflammatory effects. Aims： To investigate the potential mechanism underlying the protective effect of LXR activation on α-GalCer-induced liver injury in mice. Methods： Fifteen C57BL/6J mice were randomly divided into normal control group, α-GalCer model group and LXR treatment group, oL-GalCer was administered intraperitoneally to induce liver injury in α-GalCer model group and LXR treatment group, and LXR agonist T0901317 was given intraperitoneally to mice in LXR treatment group for 7 days before α-GalCer administration. Mice were sacrificed 6 hours after α-GalCer administration. Histopathological examination was performed on liver sections, and the serum levels of ALT and AST were measured. The hepatic interleukin-6 （IL-6） expression was assessed by immunohistochemical staining. The activation of PI3K/Akt/NF-κB signal pathway in liver was detected by Western blotting. The hepatic tumor necrosis factor-α （TNF-α） and inducible nitric oxide synthase （iNOS） mRNA expressions were determined by real-time RT-PCR. Results： Compared with normal control group, significant liver injury could be observed histopathologically in α-GalCer model group, with increased serum transaminase levels and upregulated hepatic IL-6, TNF-α and iNOS expressions, and PI3K/Akt/NF-κB signal pathway in liver was activated. In LXR treatment group the α-GalCer-induced liver injury was attenuated, serum transaminase levels were decreased, expressions of hepatic inflammatory mediators were reduced, and the activation of PI3K/Akt/NF-κB signal pathway in liver was inhibited. Conclusions： Activation of LXR can attenuate α-GalCer-induced liver injury in mice by its immune regulatory and anti-inflammatory effects. The potential mechanism might be related to inhibiting the activation of PI3K/Akt/NF-κB signal pathway.