Department of Internal Medicine, Charles R. Drew University, Los Angeles, CA, USA.
Exp Mol Pathol. 2011 Aug;91(1):419-28. doi: 10.1016/j.yexmp.2011.04.009. Epub 2011 May 3.
Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver pathologies and is associated with obesity and the metabolic syndrome. Here, we investigated the molecular mechanisms by which a novel cystine based glutathione precursor with added selenomethionine (F1) prevents hepatic steatosis in a moderate high fat dietary model of NAFLD. Adult (8 weeks old), male apolipoprotein E (ApoE)-/- mice were fed with a normal diet (ND) or high fat diet (HFD), consisting of 21% fat and 0.21% cholesterol, with or without dietary supplementation of F1 (3 g/kg food) for 16 weeks. Compared with ApoE-/- mice fed with ND with or without F1, ApoE-/- mice fed with HFD exhibited significant weight gain, hepatomegaly, and increased serum cholesterol and triglycerides levels with no change in serum albumin levels. High resolution light and electron microscopy revealed micro-and macro-vesicular steatosis in ApoE-/- mice fed on a HFD. HFD-induced obesity also led to increased lipogenesis, oxidative stress, activation of c-Jun-NH(2)-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), perturbation of the BAX/BCL-2 rheostat, hepatocyte apoptosis, and activation of caspases 9 and 3. F1 fully prevented the adverse effects of HFD on serum triglyceride levels, body and liver weights, and hepatic steatosis and substantially attenuated HFD-induced increase in lipogenesis, oxidative stress, kinase activation, apoptotic signaling, and hepatocyte ultrastructural abnormalities. These results demonstrate that administration of F1, a glutathione precursor, ameliorates HFD-induced hepatic steatosis in ApoE-/- mice and emphasizes the role of oxidative stress in diet-induced obesity and hepatic steatosis.
非酒精性脂肪性肝病（NAFLD）是最常见的肝脏疾病形式，与肥胖和代谢综合征有关。在这里，我们研究了一种新型半胱氨酸基谷胱甘肽前体与添加硒代蛋氨酸（F1）的分子机制，该前体可预防非酒精性脂肪性肝病的中度高脂肪饮食模型中的肝脂肪变性。成年（8 周龄）雄性载脂蛋白 E（ApoE）-/-小鼠用正常饮食（ND）或高脂肪饮食（HFD）喂养，HFD 由 21％的脂肪和 0.21％的胆固醇组成，并用或不用 F1（3 g/kg 食物）进行饮食补充 16 周。与用 ND 喂养的 ApoE-/-小鼠或用 F1 喂养的 ApoE-/-小鼠相比，用 HFD 喂养的 ApoE-/-小鼠体重明显增加，肝肿大，血清胆固醇和甘油三酯水平升高，而血清白蛋白水平没有变化。高分辨率光镜和电子显微镜显示，用 HFD 喂养的 ApoE-/-小鼠出现微泡和大泡性脂肪变性。HFD 诱导的肥胖还导致脂肪生成增加、氧化应激、c-Jun-NH2-末端激酶（JNK）和 p38 丝裂原活化蛋白激酶（MAPK）激活、BAX/BCL-2 变阻器失调、肝细胞凋亡和半胱天冬酶 9 和 3 的激活。F1 完全阻止了 HFD 对血清甘油三酯水平、体重和肝重以及肝脂肪变性的不良影响，并显著减轻了 HFD 诱导的脂肪生成增加、氧化应激、激酶激活、凋亡信号和肝细胞超微结构异常。这些结果表明，谷胱甘肽前体 F1 的给药可改善 ApoE-/-小鼠的 HFD 诱导的肝脂肪变性，并强调了氧化应激在饮食诱导的肥胖和肝脂肪变性中的作用。
