双酚A暴露致自噬异常诱导胰岛素抵抗的机制及其与儿童非酒精性脂肪肝关联的研究

儿童非酒精性脂肪肝病(NAFLD)正迅速成为世界范围内儿童最主要肝脏疾病, 其发病原因和机制尚不完全清楚。但肥胖是NAFLD发生最重要危险因素。最近报道在美国12-19岁青少年中，双酚A(BPA)暴露水平较高与NAFLD发病风险增高有关，而且在肥胖青少年中这种风险增高更加显著。实验研究显示BPA暴露可能直接通过触发肝脏或全身胰岛素抵抗(IR)导致NAFLD发生。但目前BPA暴露诱发IR机制不明确，而且BPA与NAFLD关系研究仅见个别报道，其潜在危害需进一步验证。因此，本项目将通过人群与实验室相结合方法，阐明BPA暴露水平对肥胖和非肥胖儿童NAFLD发生易感性的影响，并从自噬、炎症、氧化应激方面重点研究BPA暴露引起IR的机制及时间-剂量-效应关系。本项目预期为进一步阐明儿童NAFLD高发原因及机制，筛选早期儿童NAFLD高危人群生物标志物，开展早期该病防治提供新的理论依据。

Non-alcoholic fatty liver disease (NAFLD) in children is rapidly becoming the most important liver disease among children in the world, its pathogenesis and mechanism are not completely clear. But obesity is one of the most important risk factors in NAFLD. Recently, it has been reported that higher levels of bisphenol A (BPA) exposure are associated with an increased risk of NAFLD in adolescents aged 12 to 19 years in USA, and the increased risk is more significant in obese adolescents. Experimental studies show that BPA exposure may lead to NAFLD directly by triggering liver or systemic insulin resistance (IR). However, the mechanism of IR induced by BPA is unclear now, and the relationship between BPA and NAFLD has been reported only in a few cases, and its potential hazards need to verify further. Therefore, this project will be explore the effect of BPA exposure levels on the susceptibility of NAFLD in obese and non-obese childhild, and focus on the mechanism of IR induced by BPA exposure from autophagy, inflammation, oxidative stress, and its time-dose-effect relationship by human study combined with experimental research. This project is expected to provide a new theoretical basis for further elucidating the causes and mechanisms of high incidence of NAFLD in children, to screen the biomarkers for early identification of high-risk population of NAFLD in children, and to carry out the prevention and treatment of NAFLD early.