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

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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.