Pinterić, Marija
(2021)
The role of Sirtuin 3 protein in estrogen-mediated cell response mechanisms in physiological and pathophysiological conditions.
Doctoral thesis, University of Zagreb, Faculty of science.
Abstract
The relationship between Sirtuin 3 (Sirt3) and estrogen (E2) in physiological and pathophysiological conditions was studied using pharmacological, dietary and genetic approaches in vitro and in vivo. This thesis shows that both Sirt3 and hyperoxia act as a tumor-suppressors of MCF-7 breast cancer cells’ malignant properties, which is observed through their reduced proliferation, survival and mitochondrial dysfunction. Furthermore, Sirt3 negatively affects the proliferative effect of E2 causing the reduction of cells’ response to E2. Additionally, it affects p53 by disrupting the ERα–p53 interaction, inhibits cells’ clonogenic capacity and lowers their migration capacity. The studies on Sirt3 WT and KO male and female mice upon high-fat diet (HFD) show sex-specific effects of HFD through reduced Sirt3 expression only in male WT mice, alleviated lipid accumulation and reduced glucose uptake in male KO mice, pointing towards a higher reliance of males on the protective effect of Sirt3 against HFD-induced metabolic dysregulation. Moreover, HFD in combination with ovariectomy and Sirt3 depletion increases body weight gain, impairs the response of an antioxidative system, upregulates the expression of oxidative stress-inducing genes, making these females more prone to NAFLD. Overall, studies on mice highlight the importance of preclinical biomedical research on both sexes and the influence of sex hormones and Sirt3 on metabolic homeostasis.
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