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

环境污染物对肝脂毒性发展的细胞和分子影响以及运动训练的影响。

• 批准号: 418312-2012
• 负责人: Chapados, Natalie
• 金额: $ 2.11万
• 依托单位: University of Ottawa
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=551339
• 关键词: Cellular; molecular; impacts; environmental; contaminants

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.

由于它们的亲脂性，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，引发内质网（ER）应激，从而促进肝脏脂肪毒性的发展。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轻或预防肝脂毒性。然而，OC积累、内质网应激、肝脂毒性和训练效果之间的关联机制仍有待研究。通过结合细胞培养和动物模型，本研究计划的总体目标是：(1)继续推进我们对暴露于OC对肝细胞和脂肪细胞代谢活性的脂毒性作用的理解；(2)利用生理适应模型（如慢性运动）研究脂毒性的可逆性机制。它主要集中在三个主要研究领域：1)OC对肝内机制和肝脏内质网应激直接导致肝脂毒性的影响；2)OC对肝外机制和脂肪细胞内质网应激间接导致肝脂毒性的影响；3)慢性运动训练对OC暴露对肝脏和脂肪细胞代谢活性的影响。在这些研究领域中，已经确定了一些需要立即注意的尚未解决的问题。因此，本文拟开展的工作将：1)明确OC诱导肝脂毒性的分子机制，量化肝脏内质网应激途径；2)量化OC暴露的脂肪细胞中脂解、内质网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意义；3)研究慢性运动对OC暴露生物肝脏和脂肪细胞中肝脂毒性和内质网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，并提供关于慢性运动对OC暴露生物体影响的分子方面的信息。