药物性肝损伤中肝脏特异性PPARα通过IL-6/STAT3信号通路调控肝细胞凋亡增殖修复的作用及机制研究

药物性肝损伤发病率逐年上升。宿主免疫参与的机制研究欠明晰。过氧化物酶体增殖物激活受体α（PPARα）在药肝相关机制研究中均显示其重要的保护作用，但此结论并未在PPARα激动剂贝特类药物的临床使用经验中得到验证。我们前期发现药肝患者肝内PPARα表达量显著下调；与合作实验室成功构建肝细胞特异敲除PPARα小鼠（PparaΔHep）进行对乙酰氨基酚（APAP）诱导的肝损伤预实验：PparaΔHep小鼠APAP诱导肝损伤显著减轻；氧化应激降低，IL-6表达上调。基于此提出假说：肝内PPARα通过调控氧化应激和IL-6/STAT3通路，进而调控肝细胞凋亡与增殖，参与肝损伤发病机制。计划用PparaΔHep小鼠及对照Pparafl/fl小鼠APAP肝损伤模型，从APAP代谢、肝细胞氧化应激、IL-6信号通路多方面证实肝细胞PPARα在APAP肝损伤中调控机制，为靶向药物研发方向的调整提供理论依据。

The incidence of Drug-induced liver injury(DILI) is increasing year by year. But the pathogenesis involving host immune response is still not clear.Acetaminophen (APAP) overdose is a major cause of acute liver failure, resulting in mitochondrial damage-induced oxidative stress and hepatic cytotoxicity from metabolic products and signaling pathway-mediated inflammatory response. Peroxisome proliferator-activated receptor α (PPARα) is a critical nuclear receptor for controlling fatty acid metabolism. Nonspecific activation of PPARα with Wy14,643 has been reported to ameliorate APAP hepatotoxicity in wild-type (WT), but not in whole-body Ppara-/- mice, however, the exact role of hepatocyte PPARα in APAP-induced liver injury is not known. Here, hepatocyte-specific PPARα-deficient (PparaΔHep) mice and their littermate control Pparafl/fl mice were used to identify the precise role of hepatocyte PPARα in APAP-induced liver injury. After a single overdose of APAP challenge, PPARα and its target genes were reduced in WT mice. Disruption of PPARα in hepatocytes significantly alleviated APAP-induced liver injury compared to that observed in Pparafl/fl mice. Pilot studies showed that the protective role of PPARα was not due to APAP bioactivation and detoxification. Reduced production of reactive oxygen species, as shown by lower hepatic level of malondialdehyde (MDA), diminished dihydroethidium (DHE)-stained positive hepatocytes and decreased phosphorylated JNK were found in the liver from APAP-treated PparaΔHep mice compared with that in Pparafl/fl mice. Moreover, PparaΔHep mice after APAP treatment had a higher IL-6 hepatic expression than that in Pparafl/fl mice. So based on the previous results, the further study including clinical research part and basic research part will carry on to approve the hypothesis about that hepatocyte-specific disruption of PPARα plays an important protective role against APAP-induced liver injury by reducing APAP-induced oxidative stress as well as upregulating the IL-6/STAT3 signaling pathway to promote liver repair.Maybe it will help to reorientate the research and development of targeted drugs in DILI.