妊娠期尼古丁暴露对子代大鼠非酒精性脂肪肝发生发展的作用及机制研究

Prenatal intrauterine non-healthy environment exposure increases the risk of metabolic syndrome in adult offspring of the rats. Smoking (nicotine exposure) is the most common risk factor for pregnant women. However, the relationship between maternal nicotine exposure and non-alcohol fatty liver diseases (NAFLD) and its underlying mechanism remains unknown. Our previous results showed that maternal nicotine exposure (MNE) markedly enhances the susceptibility to NAFLD in adult offspring rats. In this study, we will establish a model of intrauterine growth retardation (IUGR) by exposing of pregnant rats to nicotine and will investigate the effects of MNE on hepatic inflammation, liver fatty degeneration, liver fibrosis, signaling pathways of fatty metabolism and insulin sensitivity in the offspring of MNE rats; we will investigate the effects of high fatty diets on the NAFLD susceptibility of the adult offspring rats and their mechanisms involved. Our results from this study will establish a direct relationship between MNE and NAFLD, elucidate the new mechanisms of NAFLD and provide new approaches for the prevention of NAFLD.

产前宫内不良环境暴露可增加子代日后成年期发生代谢综合征的风险。孕妇吸烟（尼古丁暴露）是目前最普遍的产前危害因素。然而，妊娠期尼古丁暴露（MNE）与日后非酒精性脂肪肝病（NAFLD）发病之间的关系仍不清楚。我们的前期研究初步发现，妊娠期尼古丁暴露可致子代大鼠成年期NAFLD易感。本项目拟通过研究不同时期（出生当日、1、3、6、12及24月龄）的MNE子代大鼠的肝脏组织的炎症反应、脂肪变性及肝纤维化、脂代谢信号通路及胰岛素敏感性的变化，探讨MNE与子代大鼠NAFLD发生的关系，阐明NAFLD发生的新机制；研究高脂饮食对MNE子代大鼠NALFD的发生发展的影响，探讨机体的先天因素（MNE）和后天因素（高脂饮食）在NAFLD发生发展中的协同作用及分子机制，从而为优生优育及预防NAFLD提供新策略。

非酒精性脂肪肝性肝病（non-alcoholic fatty liver disease，NAFLD）的发病率逐年攀升，且部分病人可进展为肝纤维化、肝硬化和肝癌。因此，研究NAFLD的发病机制由此寻求防治策略变得十分必要且迫切。本研究采用大鼠妊娠期不良宫内环境的动物模型（妊娠期缺氧及尼古丁暴露），观察到子代新生子鼠出现低出生体重（fetal growth restriction，FGR）现象，但在出生后即出现“追赶生长”现象，从而增加子代肝脏脂质含量，致子代成年期大鼠NAFLD易感，并且宫内不良环境（产前缺氧及尼古丁暴露）与子鼠成年期高脂饮食造成的脂肪肝具有协同促进效应。进一步探讨其分子机制，发现妊娠期缺氧子鼠胰岛素信号通路表达下调，引起机体胰岛素抵抗。另外，肝脏组织脂质代谢通路分子表达异常：类固醇调节元件结合蛋白(SREBP)介导的脂质合成通路上调、过氧化物酶体增殖物激活受体(PPAR-α)转录因子介导的脂质分解代谢通路表达下调，最终导致肝脏脂质合成增加、氧化分解减少，最终增加了子代对NAFLD的敏感性。综上，本研究阐明了妊娠期不良宫内环境（妊娠期缺氧）致子代NAFLD及其易感的分子机制，解析了国际前沿问题“成人疾病的胎儿起源”学说，为优生优育、为探寻NAFLD的早期防治策略提供理论及实验依据。