Repin1 and Resolvines - provocation and resolution of "silent and sterile" inflammation (inflammasome) in the progression of chronic liver diseases to HCC

代谢作用、氧化应激以及促炎性和抗炎性细胞因子的失衡在脂肪肝发展为肝细胞癌（HCC）的过程中起着特别重要的作用。在肝脏炎症过程中，NLRP3炎性小体的激活在慢性肝病的发病机制中起着至关重要的作用。因此，降低炎症状态对于预防和治疗肝脏疾病具有重要意义。在本研究中，我们分析(i)脂质调节剂（如Repin1）与脂质介质（resolvines）之间的相关性，（ii）它们在慢性肝脏疾病向HCC发展过程中对无菌炎症的调节，（iii）它们在人类中的意义，以及（iv）预防和治疗方面。本研究的目的是在临床相关的nash -纤维化-HCC小鼠实验模型中，评估肝缺乏Repin1是否通过调节nlrp3介导的炎症反应来减缓脂肪肝向HCC的进展。在此背景下，应该分析repin1诱导的代谢报警信号的产生与NLRP3的连续激活以及由于缺乏解决方案而导致的肝脏炎症的持续存在之间的功能关系。我们进一步关注脂联素作为信号通路、resolvines和NLRP3的共同因子和调节因子。此外，应该评估肝脏特异性sirna介导的Repin1或NLRP3缺乏以及抗炎介质（n-3脂肪酸（饮食），resolvines）的供应是否代表治疗和预防慢性肝病的选择。

Metabolic effects, oxidative stress, and an imbalance of pro- and anti-inflammatory cytokines are of particular importance in the progression of fatty liver to hepatocellular carcinoma (HCC). During liver inflammation activation of the NLRP3 inflammasome plays a crucial role in the pathogenesis of chronic liver diseases. Therefore, reduction of the inflammatory state is of high significance for prevention and therapy of liver diseases. In this study we analyze (i) the correlation between lipid modulators, such as Repin1 and lipid mediators (resolvines), (ii) their regulation of the sterile inflammation in the progression of chronic liver diseases to HCC, (iii) their significance in humans, and (iv) aspects for prevention and therapy. The aim of this study is to evaluate whether hepatic deficiency of Repin1 attenuates progression of fatty liver to HCC by modulating the NLRP3-mediated inflammatory response in a clinically relevant experimental NASH-Fibrosis-HCC mouse model. In this context, functional relationships between Repin1-induced generation of metabolic alarm signals and a consecutive activation of NLRP3 as well as a perpetuation of the hepatic inflammation due to the lack of resolvines should be analyzed. We further focus on adiponectin as a common factor and regulator of both signaling pathways, resolvines, and NLRP3. Moreover, it should be evaluated whether a liver-specific siRNA-mediated deficiency of Repin1 or NLRP3 as well as a supply of anti-inflammatory mediators (n-3 fatty acid (diet), resolvines) represent therapeutic and preventive options for the treatment of chronic liver diseases.