Role and Mechanisms of E4BP4 over-activation in diet-induced fatty liver disease

非酒精性肝病（NAFLD）是最常见的肝病，困扰着30%的普通人群。到目前为止，NAFDL还没有有效的治疗方法。大约10%的NAFLD患者从单纯性脂肪变性进展为非酒精性脂肪性肝炎（NASH），最终导致肝功能衰竭。对于伴有肝功能衰竭的NAFLD患者，肝移植是唯一的治疗选择。尽管富含脂肪、胆固醇和果糖的饮食与NAFLD之间存在很强的相关性，但高脂肪、高胆固醇和高果糖（HFCF）饮食促进肝脏脂肪变性、炎症和纤维化的分子机制仍然知之甚少。本提案的总体目标旨在研究b-ZIP转录抑制因子E4启动子结合蛋白4（E4 BP 4）在小鼠中驱动饮食诱导的NAFLD中的作用。我们的初步数据表明，肝脏E4 BP 4的缺失保护小鼠免受高脂饮食诱导的肝脏脂肪变性，并且E4 BP 4促进肝脏中两种主要脂滴结合蛋白Cidea和Fsp 27-β的表达以响应高脂饮食。我们还发现，慢性高脂饮食喂养导致肝脏中E4 BP 4的去SUMO化。此外，表达不可SUMO酰化的E4 BP 4的肝细胞显示出比WT-E4 BP 4更多的脂滴形成。因此，我们假设E4 BP 4去SUMO化通过增加饮食诱导的脂肪肝疾病期间的脂质生物合成和储存来促进肝脏脂肪变性及其进展。我们将通过追求以下三个具体目标来检验中心假设：1。使用肝脏特异性E4 bp 4敲除小鼠确定E4 BP 4在促进HFCF饮食诱导的NAFLD中的病理作用。2.揭示肝脏E4 BP 4如何通过在饮食诱导的NAFLD期间升高肝细胞和肝脏中Cidea和Fsp 27-β表达来促进脂质蓄积的分子途径。3.探讨肝脏E4 BP 4去SUMO化在饮食诱导的NAFLD发病机制中的作用和调节。我们的研究将揭示肝细胞特异性E4 BP 4作为连接HFCF饮食和NAFLD的关键调节因子。完成拟议的研究将获得关于E4 BP 4驱动的分子途径的关键知识，以促进NAFLD的发作和进展。这些新的知识将揭示通过靶向E4 BP 4表达或SUMO化来治疗NAFDL的新的预防或治疗措施。

Non-alcoholic liver disease (NAFLD) is the most common liver disease, afflicting 30% of the general population. So far, there has been no effective treatment for NAFDL. Approximately 10% of patients with NAFLD progress from simple steatosis to non-alcoholic steatohepatitis (NASH) and eventually live failure. For patients of NAFLD with liver failure, liver transplant is the only therapeutic option. In spite of a strong correlation between diets rich in fat, cholesterol, and fructose and NAFLD, molecular mechanisms by which high fat, high cholesterol, and high fructose (HFCF) diet promotes liver steatosis, inflammation and fibrosis remains poorly understood. The overall objective of this proposal aims to investigate the role of b-ZIP transcription repressor E4 promoter- binding protein 4 (E4BP4) in driving diet-induced NAFLD in mice. Our preliminary data demonstrated loss of hepatic E4BP4 protects mice against high-fat diet-induced liver steatosis and E4BP4 promotes the expression of Cidea and Fsp27-β, two major lipid droplet binding proteins, in the liver in response to high-fat diet. We also discovered that chronic high-fat diet feeding leads to deSUMOylation of E4BP4 in the liver. Moreover, hepatocytes expressing a non-SUMOylatable E4BP4 show more lipid droplet formation than those of WT- E4BP4. Thus, we hypothesize that E4BP4 deSUMOylation promotes liver steatosis and its progression by increasing lipid biosynthesis and storage during diet-induced fatty liver disease. We will test the central hypothesis by pursuing the following three specific aims: 1. Determine the pathologic role of E4BP4 in promoting HFCF diet-induced NAFLD using liver-specific E4bp4 knockout mice. 2. Uncover molecular pathways of how hepatic E4BP4 promotes lipid accumulation via elevating Cidea and Fsp27-β expression in hepatocytes and the liver during diet-induced NAFLD. 3. Investigate the function and regulation of deSUMOylation of hepatic E4BP4 in the pathogenesis of diet- induced NAFLD. Our study will uncover hepatocyte-specific E4BP4 as a crucial regulator that connects HFCF diet and NAFLD. The completion of the proposed study will gain critical knowledge regarding the molecular pathways driven by E4BP4 to promote the onset and progression of NAFLD. The novel knowledge will shed light on novel preventive or therapeutic measures to treat NAFDL by targeting E4BP4 expression or SUMOylation.