Cellular and molecular impacts of environmental contaminants in the development of hepatic lipotoxicity and the effects of exercise training.

由于有机氯化合物 (OC) 的亲脂性，它们会在生物体内积聚。 OC 可能与肝脏和脂肪细胞代谢相互作用，引发内质网 (ER) 应激，从而导致肝脏脂毒性的发生。有趣的是，长期运动已被证明可以通过诱导分子变化成功减轻或预防肝脏脂毒性。然而，OC 积累、内质网应激、肝脂毒性和训练效果之间关联的机制仍有待研究。通过将细胞培养和动物模型相结合，该研究项目的总体目标有两个：（1）继续推进我们对OC暴露对肝细胞和脂肪细胞代谢活动的脂毒性影响的理解；（2）利用慢性运动等生理适应模型研究脂毒性的可逆机制。它侧重于三个主要研究领域：1）OC对肝内机制和肝脏内质网应激的影响，直接导致肝脂毒性；2）OC对肝外机制和脂肪细胞内质网应激的影响，间接导致肝脂毒性；3）长期运动训练对OC暴露对肝脏和脂肪细胞代谢活动的影响。在这些研究领域中，已经确定了许多需要立即关注的未解决问题。因此，拟议的工作将：1）定义与OC诱导的肝脂毒性有关的分子机制并量化肝脏中的ER应激途径，2）量化OC暴露的脂肪细胞中的脂肪分解、ER应激分子表达和脂肪因子分泌及其在肝脂毒性发展中的潜在含义，3）检查长期运动对OC的肝脏和脂肪细胞中的肝脂毒性和ER应激途径的分子影响暴露的生物体。它将有助于确定 OC 对肝脏和脂肪细胞代谢活动的可能作用，并提供有关长期运动对 OC 暴露生物体影响的分子方面的信息。

Due to their lipophilicity, organochlorines compounds (OC) accumulate in living organisms. OC may interact with liver and adipocyte metabolisms and trigger endoplasmic reticulum (ER) stress, therefore contributing to the development of lipotoxicity in the liver. Interestingly, chronic exercise has been shown to successfully attenuate or prevent liver lipotoxicity by inducing molecular changes. However, the mechanism(s) underlying the association between OC accumulation, ER stress, hepatic lipotoxicity and the effects of training remains to be investigated. By combining cell culture and animal model, the general objective of this research program is two-fold: (1) continue advancing our understanding on the lipotoxic effects of OC exposure on hepatocyte and adipocyte metabolic activities and (2) study reversibility mechanisms of lipotoxicity using physiological adaptation models such as chronic exercise. It focuses on three main areas of research: 1) the effects of OC on intra-hepatic mechanisms and ER stress in liver leading directly to hepatic lipotoxicity, 2) the effects of OC on extra-hepatic mechanisms and ER stress in adipocytes leading indirectly to hepatic lipotoxicity, and 3) the effects of chronic exercise training on OC exposure on liver and adipocyte metabolic activities. Within these areas of research, a number of unresolved issues needing immediate attention have been identified. Thus, the proposed work will: 1) define the molecular mechanisms implicated in OC induced hepatic lipotoxicity and quantify the ER stress pathway in liver, 2) quantify lipolysis, ER stress molecules expression and adipokines secretion in OC exposed adipocytes and their potential implication in the development of hepatic lipotoxicity and 3) examine the molecular effects of chronic exercise on hepatic lipotoxicity and ER stress pathway in liver and adipocytes of OC exposed organisms. It will help establishing the possible role of OC on liver and adipocyte metabolic activities and provide information on molecular aspects of the impact of chronic exercise in OC exposed organisms.