The Imprinted Gene Network in the Programming of Non-Alcoholic Fatty Liver Disease by Early Life Cadmium Exposure

项目总结 非酒精性脂肪性肝病(NAFLD)的特征是脂肪堆积、炎症和组织 肝脏受损。NAFLD影响美国30%-40%的成年人口，NAFLD患者 罹患肝癌的风险更高。越来越多的证据支持 非酒精性脂肪肝后天生活规划的发展环境。为了支持这一点，我们有 证明在发育过程中暴露于有毒金属镉(Cd)会导致NAFLD 幼小的老鼠。Cd是世界确定的十大主要公共卫生问题化学品之一 并在新生儿脐带血中检测到，这表明镉暴露在 人类可以从子宫内发育开始。为了努力确定潜在的治疗靶点， 可预防非酒精性脂肪性肝病对发育期镉暴露的反应，我们研究了 潜在的分子机制。我们已经确定印记基因网络(IGN)是一种新的 参与激活骨质疏松症和纤维化症--这是两种主要的病理生理机制 NAFLD背后的过程。然而，尚不清楚这一机制是否是CD所特有 与更广泛的毒物有关，这些毒物也是这种疾病的程序。为了解决这个问题，我们提出了三个 具体目标：1)对小鼠模型的肝脏转录组数据集进行荟萃分析 NAFLD由发育环境编程以确定IGN是否被激活作为响应 一组不同的应激源；2)筛选毒物，以了解它们激活细胞内IGN的能力 在肝细胞中的方式；3)使用毒物暴露的体外模型来测试是否有前骨质形成和/或 促纤维化的机制依赖于IGN。这项工作将极大地增强 通过证明这一机制是特定于CD还是也与一项 更广泛的毒物种类。这将是识别可用药靶点的行动中的关键知识 可用于预防早期生命暴露后NAFLD的发病。

Project summary Non-alcoholic fatty liver disease (NAFLD) is characterized by fat accumulation, inflammation and tissue damage in the liver. NAFLD affects 30-40 % of the US adult population, and patients with NAFLD have a higher risk of developing liver cancer. An increasing body of evidence supports a role for the developmental environment in the programming of NAFLD in later life. In support of this, we have demonstrated that exposure to the toxic metal cadmium (Cd) during development causes NAFLD in young mice. Cd is one of the top ten chemicals of major public health concern identified by the World Health Organization, and it has been detected in newborn cord blood, suggesting that Cd exposure in humans can begin during in utero development. In an effort to identify potential therapeutic targets that could prevent the onset of NAFLD in response to developmental Cd exposure, we have studied the underlying molecular mechanisms. We have identified the Imprinted Gene Network (IGN) as a novel player in activating prosteatotic and profibrotic pathways – two of the major pathophysiological processes that underlie NAFLD. However, it is unclear if this mechanism is specific to Cd or if it is relevant to a broader set of toxicants that also program this disease. To address this, we propose three specific aims: 1) perform a meta-analysis of hepatic transcriptome datasets from mouse models of NAFLD programmed by the developmental environment to determine if the IGN is activated in response to a diverse set of stressors; 2) screen toxicants for their ability to activate the IGN in a cell autonomous manner in hepatocytes; 3) use in vitro models of toxicant exposure to test whether prosteatotic and/or profibrotic mechanisms are dependent on the IGN. This work will considerably enhance the impact of the parent award by demonstrating whether this mechanism is specific to Cd or also relevant to a broader set of toxicants. This will be critical knowledge in the drive to identify druggable targets that could be used to prevent the onset of NAFLD after early life exposures.