GC-SIRT1-SREBP1c信号介导孕期尼古丁暴露所致子代NAFLD易感的宫内编程机制

项目名称： GC-SIRT1-SREBP1c信号介导孕期尼古丁暴露所致子代NAFLD易感的宫内编程机制

项目编号： No.81471465

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 夏利平

作者单位： 武汉大学

项目金额： 80万元

中文摘要： 流行性病学调查提示，非酒精性脂肪肝（NAFLD）存在宫内发育起源。我们前期发现，孕期尼古丁暴露可引起仔鼠宫内发育迟缓（IUGR）及成年后代谢综合征易感，其机制与母源性糖皮质激素（GC）过暴露有关；同时发现IUGR仔鼠出生前、后肝脏SREBP1c表达升高。综合文献，我们推测：孕期尼古丁暴露所致的母源性高GC，可通过降低胎肝SIRT1表达，增加SREBP1c乙酰化修饰及表达，使肝脏脂质合成功能增强，此效应可持续至出生后，从而介导NAFLD的易感性。本项目拟在整体与细胞水平，证实孕期尼古丁暴露所致IUGR子代的NAFLD易感现象，确定胎肝GC-SIRT1-SREBP1c信号在出生后NAFLD发生、发展过程中的关键地位及其转录调控机制，并在整体动物水平对SIRT1活性进行干预。本项目将为解析胎源性NAFLD宫内编程的分子遗传机制，探寻胎源性NAFLD的药物干预靶标及早期防治策略，提供实验依据。

中文关键词： 非酒精性脂肪肝病；宫内发育迟缓；尼古丁；脂质代谢；信息沉默调节因子

英文摘要： Epidemiological investigations have showed that non-alcoholic fatty liver disease (NAFLD) has developmental origin. In our previous studies, we have discovered that prenatal nicotine exposure may enhance susceptibility to intrauterine growth retardation (IUGR) and adult metabolic syndrome, and the mechanism is relative to overexposure to maternal glucocorticoids (GC). Furthermore, we have found that the expressions of hepatic SREBP1c increased in both the fetus and IUGR offspring. Based on literature, we hypothesize that high maternal GC induced by prenatal nicotine exposure may increase acetylation and expression of SREBP1c by reducing the expression of SIRT1 in the fetal liver, and enhance lipid synthesis in the liver. The effect can continue to after birth and mediate susceptibility to NAFLD. In the present study, we will intend to confirm that the phenomenon of susceptibility to NAFLD in IUGR offspring induced by prenatal nicotine exposure, clarify the molecular genetic mechanisms of intrauterine fetal programming of NAFLD, and determine the key position and possible regulatory mechanisms of GC-SIRT1-SREBP1c signaling pathway in fetal liver in the development and progression of NAFLD. We will furtherly intervene the expression of SIRT1 in the lab animals and cell levels to explore early intervention and prevention of measures of NAFLD caused by fetal original factors and to provide experimental basis.

英文关键词： non-alcoholic fatty liver disease;intrauterine growth retardation;nicotine;lipid metabolism;silence information regulator