Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, China; State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing 100193, China.
Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, China.
Biochim Biophys Acta Mol Basis Dis. 2018 Feb;1864(2):488-498. doi: 10.1016/j.bbadis.2017.11.009. Epub 2017 Nov 17.
Serine deficiency has been observed in patients with nonalcoholic fatty liver disease (NAFLD). Whether serine supplementation has any beneficial effects on the prevention of NAFLD remains unknown. The present study was conducted to investigate the effects of serine supplementation on hepatic oxidative stress and steatosis and its related mechanisms. Forty male C57BL/6J mice (9week-old) were randomly assigned into four groups (n=10) and fed: i) a low-fat diet; ii) a low-fat diet supplemented with 1% (wt:vol) serine; iii) a high-fat (HF) diet; and iv) a HF diet supplemented with 1% serine, respectively. Palmitic acid (PA)-treated primary hepatocytes separated from adult mice were also used to study the effects of serine on oxidative stress. The results showed that serine supplementation increased glucose tolerance and insulin sensitivity, and protected mice from hepatic lipid accumulation, but did not significantly decreased HF diet-induced weight gain. In addition, serine supplementation protected glutathione (GSH) antioxidant system and prevented hypermethylation in the promoters of glutathione synthesis-related genes, while decreasing reactive oxygen species (ROS) in mice fed a HF diet. Moreover, we found that serine supplementation increased phosphorylation and S-glutathionylation of AMP-activated protein kinase α subunit (AMPKα), and decreased ROS, malondialdehyde and triglyceride contents in PA-treated primary hepatocytes. However, while AMPK activity or GSH synthesis was inhibited, the abovementioned effects of serine on PA-treated primary hepatocytes were not observed. Our results suggest that serine supplementation could prevent HF diet-induced oxidative stress and steatosis by epigenetically modulating the expression of glutathione synthesis-related genes and through AMPK activation.
在非酒精性脂肪性肝病（NAFLD）患者中观察到丝氨酸缺乏。丝氨酸补充是否对预防 NAFLD 有任何有益影响尚不清楚。本研究旨在探讨丝氨酸补充对肝氧化应激和脂肪变性的影响及其相关机制。40 只雄性 C57BL/6J 小鼠（9 周龄）被随机分为四组（n=10），分别喂食：i）低脂饮食；ii）低脂饮食补充 1%（wt:vol）丝氨酸；iii）高脂肪（HF）饮食；iv）HF 饮食补充 1%丝氨酸。还使用从成年小鼠分离的棕榈酸（PA）处理的原代肝细胞来研究丝氨酸对氧化应激的影响。结果表明，丝氨酸补充可提高葡萄糖耐量和胰岛素敏感性，防止肝脏脂质积累，但不能显著降低 HF 饮食引起的体重增加。此外，丝氨酸补充可保护谷胱甘肽（GSH）抗氧化系统，防止谷胱甘肽合成相关基因启动子的过度甲基化，同时减少 HF 饮食喂养小鼠的活性氧（ROS）。此外，我们发现丝氨酸补充可增加 AMP 激活蛋白激酶α亚单位（AMPKα）的磷酸化和 S-谷胱甘肽化，并降低 PA 处理的原代肝细胞中的 ROS、丙二醛和甘油三酯含量。然而，当 AMPK 活性或 GSH 合成受到抑制时，丝氨酸对 PA 处理的原代肝细胞的上述作用则不会观察到。我们的结果表明，丝氨酸补充可通过表观遗传调节谷胱甘肽合成相关基因的表达和通过 AMPK 激活来预防 HF 饮食引起的氧化应激和脂肪变性。
