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

由于它们的亲油性，有机氯化合物（OC）在生物体中积累。OC可能与肝脏和脂肪细胞代谢相互作用并触发内质网（ER）应激，因此有助于肝脏中脂毒性的发展。有趣的是，长期运动已被证明可以通过诱导分子变化成功地减弱或预防肝脏脂毒性。然而，OC蓄积、ER应激、肝脂毒性和训练效果之间的相关机制仍有待研究。通过细胞培养和动物模型相结合，本研究计划的总体目标有两个方面：（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效应的理解;（2）使用生理适应模型（如慢性运动）研究脂毒性的可逆性机制。它集中在三个主要研究领域：1）OC对肝内机制和肝脏ER应激直接导致肝脏脂毒性的影响，2）OC对肝外机制和脂肪细胞ER应激间接导致肝脏脂毒性的影响，以及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。在这些研究领域内，已经查明了一些需要立即注意的尚未解决的问题。因此，拟议的工作将：1）确定与OC诱导的肝脂毒性有关的分子机制，并定量肝脏中的ER应激途径，2）定量脂解，OC暴露后脂肪细胞ER应激分子的表达和脂肪因子的分泌及其在肝脂毒性形成中的意义研究慢性运动对OC暴露生物体的肝脏和脂肪细胞中的肝脏脂毒性和ER应激途径的分子效应。这将有助于确定OC对肝脏和脂肪细胞代谢活动的可能作用，并提供有关OC暴露生物体中慢性运动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.