氧化型DJ-1通过结合甘油三酯脂肪酶（ATGL）在肝再生中的作用和分子机制研究

肝再生能力不足是临床上导致肝切或肝移植预后不佳的主要原因之一，也是亟待解决的重要科学问题。研究表明，肝切后瞬时再生性肝内脂肪堆积和堆积脂肪的及时水解利用对肝再生起促进作用。我们之前研究发现，DJ-1在多种肝脏疾病中起重要作用，但DJ-1是否参与肝再生目前尚不清楚。通过小鼠2/3肝切模型，我们发现肝再生过程中1）野生型小鼠肝内DJ-1特别是氧化型DJ-1（oxDJ-1）水平显著上升；2）DJ-1-/-小鼠肝再生能力明显降低；3）DJ-1-/-小鼠肝内甘油三酯脂肪酶（ATGL）水平显著下降，并伴随肝内堆积脂肪水解延迟；4）oxDJ-1可与ATGL结合。基于以上结果，我们推测oxDJ-1可结合并稳定ATGL，从而加速堆积脂肪的水解利用，促进肝再生。我们拟从脂代谢角度出发，揭示DJ-1通过ATGL影响肝再生的分子机制，研究靶向DJ-1促进肝再生的可能性。该研究将为促进肝再生提供新的靶点及治疗手段。

Liver regeneration insufficiency is one of the main causes of poor prognostic after liver resection or transplantation. Therefore, how to promote liver regeneration ability is a long-standing scientific challenge for liver surgery and transplantation. Some previous studies indicate that transient regeneration-associated steatosis(TRAS) and its prompt hydrolysis or utilization are essential for promoting liver regeneration. In addition, we have demonstrated that DJ-1 is deeply involved in the development and progression of various liver diseases, including fibrosis, hepatocellular carcinoma and ductal reaction. However, whether DJ-1 plays a role in liver regeneration is still unknown. By using a 2/3 partial hepatectomy (PHx) model, we find that the levels of DJ-1 especially of the oxidative DJ-1 (oxDJ-1) are significantly increased in the liver of wild-type (WT) mice. Compared to WT mice, DJ-1 knockout (DJ-1 KO) mice showed markedly impaired liver regeneration ability. Meanwhile, the expression level of ATGL, an important phospholipase in charge of the hydrolysis of triglyceride to diglyceride, is decreased in the liver of DJ-1 KO mice. Interestingly, such an ATGL expression decrease occurs at the protein level but not the mRNA level. Furthermore, we demonstrate that the oxDJ-1 but not the DJ-1 interacts with ATGL. According to those findings, we hypothesize that oxDJ-1 can interact ATGL to increase its stability, resulting in the prompt utilization of TRAS and enhanced liver regeneration. To test our hypothesis, we will further characterize the interaction between oxDJ-1 and ATGL，dissect the underlying mechanism of how oxDJ-1-mediated ATGL stabilization promotes liver regeneration and evaluate the potential of targeting DJ-1 in promoting liver regeneration. This study will provide us novel targets and strategies for liver regeneration enhancement.