The prevalence and severity of nonalcoholic fatty liver disease (NAFLD) is higher in men and postmenopausal women compared to premenopausal women, suggesting a protective role for ovarian hormones. Diet-induced obesity and fatty acids surplus promote mitochondrial dysfunction in liver, triggering oxidative stress and activation of c-Jun N-terminal kinase (JNK) which has been related to the development of insulin resistance and steatosis, the main hallmarks of NAFLD. Considering that estrogen, in particular 17β-estradiol (E2), have been reported to improve mitochondrial biogenesis and function in liver, our aim was to elucidate the role of E2 in preventing fatty acid-induced insulin resistance in hepatocytes through modulation of mitochondrial function, oxidative stress and JNK activation. An in vivo study was conducted in Wistar rats of both sexes (n = 7) fed control diet and high-fat diet (HFD), and in vitro studies were carried out in HepG2 cells treated with palmitate (PA) and E2 for 24 h. Our HFD-fed male rats showed a prediabetic state characterized by greater systemic and hepatic insulin resistance, as well as higher lipid content in liver, compared to females. JNK activation rose markedly in males in response to HFD feeding, in parallel with mitochondrial dysfunction and oxidative stress. Consistently, in PA-exposed HepG2 cells, E2 treatment prevented JNK activation, insulin resistance and fatty acid accumulation. Altogether, our data highlights the importance of E2 as a mitigating factor of fatty acid-insulin resistance in hepatocytes through downregulation of JNK activation, by means of mitochondrial function improvement.

中文翻译：

---

17β-雌二醇改善了脂毒性诱导的肝线粒体氧化应激和胰岛素抵抗。

与绝经前女性相比，男性和绝经后女性的非酒精性脂肪肝疾病（NAFLD）的患病率和严重性更高，表明其对卵巢激素具有保护作用。饮食引起的肥胖和脂肪酸过多会促进肝脏线粒体功能障碍，触发氧化应激并激活c-Jun N末端激酶（JNK），这与NAFLD的主要特征胰岛素抵抗和脂肪变性有关。考虑到已报道雌激素，尤其是17β-雌二醇（E2）可以改善肝线粒体的生物发生和功能，因此我们的目的是阐明E2通过调节线粒体功能来预防肝细胞脂肪酸诱导的胰岛素抵抗，氧化应激和JNK激活。在接受对照饮食和高脂饮食（HFD）的雌雄同体（n = 7）的Wistar大鼠中进行了一项体内研究，并在用棕榈酸酯（PA）和E2处理的HepG2细胞中进行了24小时的体外研究。与雌性相比，我们由HFD喂养的雄性大鼠表现出糖尿病前期状态，其特征在于更高的全身性和肝性胰岛素抵抗以及肝脏中更高的脂质含量。响应HFD喂养，男性的JNK激活显着增加，与线粒体功能障碍和氧化应激同时出现。一致地，在暴露于PA的HepG2细胞中，E2处理阻止了JNK活化，胰岛素抵抗和脂肪酸蓄积。总之，我们的数据强调了E2作为通过线粒体功能改善而下调JNK激活来减轻肝细胞脂肪酸-胰岛素抵抗的重要因素。