刺五加酸激活LXRs调控肝纤维化炎性反应的研究

肝纤维化是各种刺激因素所致慢性肝损伤的可逆修复过程，肝星状细胞（HSC）活化是肝纤维化发生的关键环节。阻断或逆转肝纤维化是预防病情进展的有效途径，但目前临床药物治疗效果不理想。多数肝纤维化由炎症诱发，炎症反应贯穿疾病整个过程。肝X受体（LXRs）是细胞核受体超家族的成员之一，激活LXRs可直接抑制炎性细胞因子的产生而发挥抗炎作用。不同LXR激动剂可诱导活化HSC由纤维形成状态逆转为静息表型。基于LXR的抗炎和调控纤维形成特性，LXRs有望成为治疗肝纤维化的一个潜在药物作用新靶点。刺五加酸近年被认为是一种天然LXRs激动剂，前期研究表明其可特异性抑制HSC活化。本研究拟对刺五加酸激活LXRs调控肝纤维化炎性反应的分子作用机制进行深入研究，明确其对TLR4-IKK-NF-κB等信号通路的调控以及与SHP、AMPK等的相互影响。

Hepatic fibrosis is a reversible reparative process of chronic hepatic injury caused by multiple stimulating factors, and activation of hepatic stellate cell (HSC) is the key point in hepatic fibrosis. Blocking and reversing of hepatic fibrosis is the effective way to prevent the progress of the disease. However, clinical medication is not ideal up to now. Most hepatic fibrosis is induced by inflammation, and inflammation penetrates the whole process of disease. Liver X-activated receptors (LXRs) are the members of nuclear receptor superfamily. Activation of LXRs directly inhibits the production of inflammatory cytokines. LXRs agonists induce activated HSC from fibrogenesis to resting phenotype. In view of inflammation and fibrogenesis regulation, LXRs could be a new potential drug action target for treatment of hepatic fibrosis. Acanthoic acid (AA) might be a natural LXRs agonist. Our prior study found that AA could specifically inhibit activation of HSC. The study would focus on molecular mechanism of activated LXRs induced by AA in regulation of hepatic fibrosis, interaction of TLR4-IKK-NF-κB signaling pathway, SHP and AMPK.