Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia.
Division of Materials Chemistry, Ruđer Bošković Institute, 10000 Zagreb, Croatia.
Int J Mol Sci. 2021 Apr 20;22(8):4277. doi: 10.3390/ijms22084277.
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 , 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.
高脂肪饮食（HFD）是代谢性疾病发展的一个重要因素，作为代谢中心的肝脏高度暴露于其影响之下。然而，HFD 诱导的代谢应激对卵巢激素耗竭和 Sirtuin 3（Sirt3）的影响尚不清楚。在这里，我们研究了 Sirt3 在卵巢切除和假手术雌性小鼠肝脏中的作用，这些小鼠在标准脂肪饮食（SFD）或 HFD 喂养 10 周后。通过 Folch、气相色谱和脂质氢过氧化物分析、组织学和油红染色、RT-PCR、Western blot、抗氧化酶和耗氧分析来检查肝脏。在 SFD 喂养的 WT 小鼠中，卵巢切除增加了 Sirt3 和脂肪酸合成，维持了线粒体功能，并降低了脂质氢过氧化物的水平。卵巢切除和 Sirt3 耗竭的组合降低了 Sirt3、Scd-1 比值、MUFA 比例、CII 驱动的呼吸作用，并增加了脂质损伤。HFD 损害了 sham 小鼠的 CII 驱动的呼吸作用，并激活了过氧化物酶体 ROS 清除酶过氧化氢酶，而与卵巢切除和 Sirt3 耗竭相结合，则增加了体重增加、NAFLD 和氧化应激诱导基因的表达，并损害了抗氧化系统的反应。总的来说，这项研究提供了证据，表明女性激素和 Sirt3 的联合作用有助于保护雌性小鼠免受 HFD 的有害影响，从而为代谢综合征和相关疾病的可能性别相关治疗药物的临床前研究做出了贡献。
