钙结合蛋白S100A11在非酒精性脂肪肝发生发展中的作用机理研究

In the past decades, non-alcoholic fatty liver disease (NAFLD) has been becoming one of the most severe live diseases to threaten human health in China and worldwide. However, due to its complicacy, the pathogenesis of NAFLD still remains less understandable. In order to explore new key factors involved in the pathogenesis of NAFLD, we carried out a proteomics analysis of tree shrew liver steatosis induced by high fat and high cholesterol diet. We found that the expression of calcium binding protein S100A11 was up-regulated gradually in a time-dependent manner, suggesting that S100A11 may be a new pathogenic factor involved in the progress of NAFLD. Therefore, we here proposed this project to characterize the roles of S100A11 in the pathogenesis of NAFLD. First, we will study the effects of S100A11 on fat accumulation through overexpression of S100A11 in vitro and in vivo. Second, we will explore the mechanisms of fat storage regulation by S100A11 through these approaches including the relationship between S100A11 and well-known lipid metabolic genes/proteins, as well as searching for proteins that interact with S100A11 by CO-IP technology. Third, we will investigate whether S100A11 also plays a key role in the transition of steatosis to steatohepatitis, and even to liver fibrosis? Taken together, these works will not only provide new insights into our understanding of the underlying mechanisms of NAFLD, but also may bring new strategy for treatment of NAFLD.

近年来，非酒精性脂肪肝的发病率逐渐增高，已成为严重威胁人类健康的重大慢性代谢性疾病。然而，由于其复杂性，非酒精性脂肪肝的发病机制至今还不是十分清楚。为了寻找发病过程中的关键因子，我们前期在树鼩非酒精性脂肪肝模型上开展了肝脏蛋白质组学研究，发现钙结合蛋白S100A11的表达与树鼩非酒精性脂肪肝的病程发展正相关，提示S100A11可能是一个新的非酒精性脂肪肝致病因子。因此，在本项目中，我们计划展开如下研究：1）细胞和动物上过表达S100A11，研究其对肝细胞脂肪积累的影响；2）探索S100A11调控脂肪储存的机制，包括S100A11与目前已知的调控脂代谢基因/蛋白的关系，以及CO-IP寻找新的与S100A11相互作用蛋白；3）S100A11在脂肪性肝炎、纤维化中的作用及分子机理？通过上述研究，本项目期望揭示非酒精性脂肪肝新的发病机理，并为非酒精性脂肪肝的治疗提供新的思路和策略。

非酒精性脂肪肝病（NAFLD）在全球人群范围内广泛发病，其包含一系列渐进性的病程，包括单纯性脂肪肝、脂肪性肝炎、肝纤维化、甚至肝硬化等。虽然目前针对脂肪肝的发病已经有诸多研究在开展，但由于其病因的复杂性，目前人们尚未透彻了解其发病机制，因此，亟需对其进一步的探索和关注。S100A11在脊椎动物中高度保守，目前对S100A11在人类疾病方面的研究大多数都集中在肿瘤领域，对其在脂质代谢领域，尤其是在NAFLD中的研究鲜有报道。. 本项目中，我们主要研究了S100A11蛋白在NAFLD发病过程中的作用及其致病机制，我们发现：1）S100A11是脂肪肝的致病因子，其在包括人类在内的各种脂肪肝模型中高表达，外源过表达S100A11会在小鼠和细胞模型中诱导细胞脂肪积累；2）S100A11高表达最终激活肝细胞内脂肪合成途径，诱导细胞内脂肪积累并发展成为脂肪肝；3）S100A11过表达会竞争性的结合HDAC6，进而激活FOXO1及其介导的自噬过程；4）抑制FOXO1和自噬或删除Dgat2可减轻S100A11诱导的脂质积累；5）S100A11在不同的肝纤维化模型中表达上调；6）肝脏特异性过表达S100A11会加剧肝纤维化疾病程度，反之，肝脏特异性敲低S100A11能缓解肝纤维化症状；7）S100A11与ANXA2形成复合物调节TGF-β信号通路并影响纤维化基因的表达；8）S100A11在肝纤维化患者血液中的浓度显著升高；9）S100A11在非酒精性脂肪性肝炎中高表达。. 本项目的实施使我们了解到S100A11是一个重要的NAFLD致病因子，它可以促进脂肪肝、脂肪性肝炎和肝纤维化的发生。我们解析出的相关分子机制不但拓宽了我们对NAFLD发病机制的理解，而且为NAFLD的治疗提供了新的思路，同时也有望推动S100A11作为新的肝纤维化临床诊断指标。