基于核受体研究IL-33在免疫性肝损伤中下调羧酸酯酶的机制

Immune abnormality-induced liver metabolism disorders are the current topic in medical researches, while the underlying mechanism remains difficult to be revealed. Liver carboxylesterase (CES) plays an important role in lipid and glucose homeostasis, as well as the metabolism of drugs and toxins. Our previous studies found that the expression and activity of CES were significantly reduced in rats with immunologic liver injury induced by lipopolysaccharide (LPS), which could be alleviated by inhibiting the markedly elevated IL-33 in the hepatic inflammation. The international and domestic relevant studies suggested that IL-33 was a major driver in the pathogenesis of hepatic inflammatory. IL-33 can combine with numerous nuclear receptors (NRs) that can also regulate the activity of CES, and the expressions of those NRs have been demonstrated to be significantly affected in immunologic liver injury. Thus, we propose that the pathway “IL-33—NRs—CES” is an ideal explanation for metabolic abnormalities of CES in the liver. In this project, we will use hepatic cells, IL-33 knock-out rats and classic LPS-induced immunologic liver injury animal model to confirm that IL-33 down regulates CES at the molecular, cellar and whole animal levels, to explore the targeted NRs that connect IL-33 and CES, and to elucidate the molecular mechanism by which IL-33 regulates the targeted NRs. Our research will clarify the intrinsic mechanism for CES metabolic disorders in immunologic liver injury and provide the theoretical basis for its intervention and treatment.

免疫异常所致肝脏代谢障碍是医学的持续研究热点，但其深入机制的研究难有突破。羧酸酯酶（CES）在肝脏糖脂、药物和毒物等物质代谢中发挥关键作用。我们前期发现脂多糖（LPS）诱导的免疫性肝损伤大鼠体内CES的表达和活性显著降低，而拮抗肝脏炎症中异常升高的IL-33可有效缓解CES的下调。国内外研究发现IL-33是肝脏炎症的重要促发元件，它可与调控CES的多种核受体结合而发挥作用，而免疫性肝损伤中亦发现上述核受体的显著改变。因此我们提出“IL-33―核受体―CES”导致肝脏代谢异常的假说。本项目拟运用细胞、IL-33基因敲除大鼠和经典的LPS诱导免疫性肝损伤模型，从分子、细胞、整体等多层面验证IL-33下调CES作用的同时，深入挖掘联系IL-33和CES之间的目标核受体，并阐明IL-33调控目标核受体的分子机理，最终揭示肝脏免疫异常中CES代谢障碍的内在机制，为其干预和治疗提供理论依据。

肝脏免疫异常所致的代谢障碍一直为医学研究热点，但目前其内在的分子机制研究不足，是开发相应干预措施的瓶颈所在。本课题组在证实免疫性肝损伤中羧酸酯酶（CES）的活性以及表达下调后，发现IL-33在免疫性肝损伤中对该代谢酶的异常变化起到关键作用。进一步地，基于核受体对CES的调控作用，我们筛选出在免疫性肝损伤中变化显著的核受体PXR、CAR，并且证实了免疫性肝损伤状态下PXR是联系IL-33和CES的“目标核受体”。.此外，我们的研究表明IL-33既可以作为胞内核因子与PXR的启动子结合发挥下调CES的作用，也可以发挥其细胞外炎性因子的作用，与其受体ST2结合激活下游信号通路影响转录因子NF-κB的表达从而间接抑制CES的表达。总之，本研究以作为肝脏炎症反应加剧的始动促发因素IL-33为起点，发现肝脏代谢酶CES活性以及表达下降，从IL-33作为转录因子直接与核受体结合以及作为细胞因子间接调控核受体的表达两个角度阐述了其下调CES的分子机制，最终阐明了免疫性肝损伤中CES代谢异常的机制，为进一步研究干预和治疗措施提供理论基础，也为临床中免疫学肝损伤患者的个体化药物治疗提供实验依据。