Abstract
High fat diet (HFD) is an important factor in the development of metabolic diseases, with liver as metabolic center being highly exposed to its influence. However, the effect of HFD-induced metabolic stress with respect to ovary hormone depletion and sirtuin 3 (Sirt3) is not clear. Here we investigated the effect of Sirt3 in liver of ovariectomized and sham female mice upon 10 weeks of feeding with standard-fat diet (SFD) or HFD. Liver was examined by Folch, gas chromatography and lipid hydroperoxide analysis, histology and oil red staining, RT-PCR, Western blot, antioxidative enzyme and oxygen consumption analyses. In SFD-fed WT mice, ovariectomy increased Sirt3 and fatty acids synthesis, maintained mitochondrial function, and decreased levels of lipid hydroperoxides. Combination of ovariectomy and Sirt3 depletion reduced pparα, Scd-1 ratio, MUFA proportions, CII-driven respiration, and increased lipid damage. HFD compromised CII-driven respiration and activated peroxisomal ROS scavenging enzyme catalase in sham mice, whereas in combination with ovariectomy and Sirt3 depletion, increased body weight gain, expression of NAFLD- and oxidative stress-inducing genes, and impaired response of antioxidative system. Overall, this study provides evidence that protection against harmful effects of HFD in female mice is attributed to the combined effect of female sex hormones and Sirt3, thus contributing to preclinical research on possible sex-related therapeutic agents for metabolic syndrome and associated diseases.
Highlights
The metabolic syndrome is a cluster of risk factors responsible for the development of cardiovascular diseases and many other health problems, and as such is one of the leading risks for global deaths representing a serious threat to public health [1]
Following high fat diet (HFD), KO normalized ovx-induced (** p < 0.01) pgc1-α gene expression. These data indicate that ovx induces both pgc1-α and sirtuin 3 (Sirt3) in WT mice irrespective of diet and that expression of the pgc1-α in ovx KO mice depends on the type of diet
standard-fat diet (SFD) and HFD, we investigated whether combination of Sirt3 depletion and ovx affected genes involved in the lipid metabolism and oxidative stress, i.e., peroxisome proliferatorgenes involved in the lipid metabolism and oxidative stress, i.e., peroxisome proliferatoractivated receptor alpha [17], cytochrome P450 4a14, cyp2e1 [18], and activated receptor alpha [17], cytochrome P450 4a14, cyp2e1 [18], and heme heme oxygenase-1 oxygenase-1
Summary
The metabolic syndrome is a cluster of risk factors responsible for the development of cardiovascular diseases and many other health problems, and as such is one of the leading risks for global deaths representing a serious threat to public health [1]. A high fat diet (HFD) is an important factor in the development of many metabolic diseases, with liver as a metabolic center being highly exposed to its influence [2]. Metabolic syndrome can be effectively mimicked and studied in rodent models using various dietary interventions, including HFD [3], which lead to mitochondrial dysfunction and other metabolic changes induced by oxidative stress (reviewed in [1]). Females show lower incidence of some age-related pathologies linked with oxidative stress and this sex-difference disappears after menopause, which leads to the conclusion that this protection is attributed to sex hormones (reviewed in [8]). Previous studies established the association of metabolic syndrome and E2 loss during menopause in women (reviewed in [9]) and reported that E2 can alter hepatic proteins involved in de novo lipid synthesis [10]. The mechanism behind those observations, especially how the fat-lowering action of E2 is modulated in the liver, remains elusive, especially in a sex-related manner
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