Li Ling, Zhang Guo-Fang, Lee Kwangwon, Lopez Rocio, Previs Stephen F, Willard Belinda, McCullough Arthur, Kasumov Takhar
Department of Research Core Services, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA.
Department of Nutrition, Case Western Reserve University, Cleveland, OH 44106, USA.
Free Radic Biol Med. 2016 Jul;96:13-21. doi: 10.1016/j.freeradbiomed.2016.03.032. Epub 2016 Mar 30.
Oxidative stress plays a key role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Glutathione is the major anti-oxidant involved in cellular oxidative defense, however there are currently no simple non-invasive methods for assessing hepatic glutathione metabolism in patients with NAFLD. As a primary source of plasma glutathione, liver plays an important role in interorgan glutathione homeostasis. In this study, we have tested the hypothesis that measurements of plasma glutathione turnover could be used to assess the hepatic glutathione metabolism in LDLR(-/)(-) mice, a mouse model of diet-induced NAFLD. Mice were fed a standard low fat diet (LFD) or a high fat diet containing cholesterol (a Western type diet (WD)). The kinetics of hepatic and plasma glutathione were quantified using the (2)H2O metabolic labeling approach. Our results show that a WD leads to reduced fractional synthesis rates (FSR) of hepatic (25%/h in LFD vs. 18%/h in WD, P<0.05) and plasma glutathione (43%/h in LFD vs. 21%/h in WD, P<0.05), without any significant effect on their absolute production rates (PRs). WD-induced concordant changes in both hepatic and plasma glutathione turnover suggest that the plasma glutathione turnover measurements could be used to assess hepatic glutathione metabolism. The safety, simplicity, and low cost of the (2)H2O-based glutathione turnover approach suggest that this method has the potential for non-invasive probing of hepatic glutathione metabolism in patients with NAFLD and other diseases.
氧化应激在非酒精性脂肪性肝病（NAFLD）的发病机制中起关键作用。谷胱甘肽是参与细胞氧化防御的主要抗氧化剂，然而目前尚无简单的非侵入性方法来评估NAFLD患者的肝脏谷胱甘肽代谢。肝脏作为血浆谷胱甘肽的主要来源，在器官间谷胱甘肽稳态中起重要作用。在本研究中，我们检验了以下假设：测量血浆谷胱甘肽周转率可用于评估饮食诱导的NAFLD小鼠模型LDLR(-/-)小鼠的肝脏谷胱甘肽代谢。给小鼠喂食标准低脂饮食（LFD）或含胆固醇的高脂饮食（西式饮食（WD））。使用(2)H2O代谢标记方法对肝脏和血浆谷胱甘肽的动力学进行定量。我们的结果表明，WD导致肝脏（LFD组为25%/小时，WD组为18%/小时，P<0.05）和血浆谷胱甘肽（LFD组为43%/小时，WD组为21%/小时，P<0.05）的分数合成率（FSR）降低，而对其绝对生成率（PRs）没有任何显著影响。WD诱导的肝脏和血浆谷胱甘肽周转率的一致变化表明，血浆谷胱甘肽周转率测量可用于评估肝脏谷胱甘肽代谢。基于(2)H2O的谷胱甘肽周转率方法的安全性、简单性和低成本表明，该方法有可能用于非侵入性探测NAFLD患者和其他疾病患者的肝脏谷胱甘肽代谢。
