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The effect of Sirt3 and gender in acute and chronic oxidative stress response in mice

Eating a “western diet” — high in fat and sugars — is associated with accelerated development of age-related metabolic diseases including metabolic syndrome defined by obesity, insulin resistance, hyperlipidemia, hyperglycemia, and hypertension. Although the association between diet, disease and age has been observed in many model organisms, the underlying molecular mechanisms remain to be elucidated. Mitochondria are an important site of intermediary metabolism within the cell, and its dysfunction is associated with a number of metabolic diseases. Sirtuin 3 (Sirt3) is protein localized primarily in mitochondria, where it modulates cellular functions, such as nutrient metabolism, ATP balance, antioxidant machinery and other mechanisms fundamental to mitochondria. It is the only member of Sirt family linked to longevity in humans. In addition, important cellular and mitochondrial processes, including reactive oxygen species (ROS) generation are integrated through Sirt3. Sirt3 plays a role in preventing metabolic syndrome, although it is not clear whether this protection is accomplished via alleviation of oxidative stress or modification of other signaling events in the cell. To better understand the mechanisms through which Sirt3 influences mitochondrial function we are investigating the role of Sirt3 and sex difference in in vivo model of Sirt3+/+ (WT) and Sirt3-/- (KO) mice. For this purpose we are exposing mice to acute (hyperoxia) and chronic (high fat diet, HFD) oxidative stress. We will determine the effect of Sirt3 and gender on survival rate after hyperoxic exposure. As a model of chronic oxidative stress we are feeding Sirt3+/+ and Sirt3-/- mice of both sexes with standard chow diet or HFD and monitoring weight gain and glucose levels once a week. After the defined period of HFD we will determine mitochondrial bioenergetic capacity of liver mitochondria with Clark type electrode. We will also determine oxidative status by measuring protein carbonyls and lipid peroxidation, but also antioxidant enzymes activity and expression levels of targeted proteins. Successful completion of these experiments will contribute to mechanistic understanding of the role of Sirt3 in mitochondrial function in oxidative stress response and nutritional challenges.

sirtuin 3 ; high fat diet ; sex differences ; mice ; oxidative stress ; metabolic stress

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