真核生物翻译起始因子5A(eIF5A)在非酒精性脂肪性肝病发病中的作用及机制

Nonalcoholic fatty liver disease (NAFLD) is a clinical syndrome characterized as no history of excessive drinking,fatty degeneration of liver cells and lipid storage. Nowadays its incidence is rising. Inducible nitric oxide (iNOS) plays an important role in its development by means of increasing insulin resistance and oxidative stress. Recent study showed that the activation of eukaryotic translation initiation factor(eIF5A) is related with iNOS expression.Knockdown of eIF5A as well as inhibition of its activation lead to alleviate inflammation of islet cells in mouse models of diabetes. Our group finds that deoxyhypusine synthase(DHPS),which is the rate-limiting enzyme of eIF5A activation, is higher in NAFLD group than normal group.We propose the activation of eIF5A is also crucial to expression of iNOS in NAFLD.Our research focus on iNOS in the pathogenesis of NAFLD and intend to answer the following questions:1)the relationship between eIF5A activation and iNOS expression;2)the mechanism of them. Through research,We will provide new discoveries on pathogenesis of NAFLD and thus provide new ways for its prevention.

非酒精性脂肪性肝病(NAFLD) 是一种无过量饮酒史，以肝细胞脂肪变性和脂质贮积为特征的临床病理综合征，其发病率逐年上升。诱导型一氧化氮(iNOS)通过增加胰岛素抵抗及氧化应激在其发病过程中发挥重要作用。研究表明，糖尿病小鼠模型中真核生物翻译起始因子5A(eIF5A)的活化和iNOS的表达密切相关，敲除eIF5A基因或抑制其活化能减轻胰岛细胞炎症。我们小组研究发现eIF5A活化过程重要的限速酶脱氧辅蛋白合成酶（DHPS）在NAFLD患者中较正常对照高表达。我们创新性提出iNOS在NAFLD的发病过程中同样受eIF5A活化的影响。本研究以NAFLD发病机制中的iNOS为研究对象，拟回答以下科学问题： 1）明确eIF5A的活化与iNOS的表达是否存在相关性；2）探索eIF5A的活化与iNOS表达之间联系的机制。通过研究，尝试就NAFLD的发病机制提供新发现进而为其防治提供新途径。

非酒精性脂肪性肝病（NAFLD）是一种除外酒精和其他明确的损肝因素所致的肝细胞内脂肪过度沉积为主要特征的临床病理综合征，其发病率逐年上升，发病机制尚未完全明确。该研究以真核细胞翻译起始因子5A (eIF5A)活化因子脱氧辅蛋白合成酶（DHPS）为切入点，观察其在 NAFLD发病中的作用及其机制。研究发现：脂肪肝模型小鼠较对照组DHPS表达量明显升高（p<0.05），以肝脏、脂肪为主(p<0.01)；DHPS过表达小鼠较GFP对照组在脂肪造模后肝内脂肪变性更明显(p<0.05)，其可能与胰岛素抵抗（Irs1）、脂肪酸合成增加（Ascbg2）及炎症因子（iNos, IL-6）相关；NAFLD患者较健康人群DHPS表达增多(p<0.05)，且与肝细胞脂肪变性呈正相关((r=0.5927,p=0.018)；人肝细胞系HL-7702脂肪造模后(OP2:1)DHPS表达显著升高。综上所述，DHPS在脂肪肝小鼠模型、NAFLD患者及脂肪造模HL-7702中均有高表达，DHPS过表达能加速肝内脂肪沉积，提示其在NAFLD发病中发挥重要作用，为其临床诊治提供新的思路。