Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892-9410, USA.
Free Radic Biol Med. 2009 Sep 15;47(6):767-78. doi: 10.1016/j.freeradbiomed.2009.06.017. Epub 2009 Jun 17.
The peroxisome proliferator-activated receptor-alpha (PPARalpha) regulates lipid homeostasis, particularly in the liver. This study was aimed at elucidating the relationship between hepatosteatosis and oxidative stress during fasting. Fasted Ppara-null mice exhibited marked hepatosteatosis, which was associated with elevated levels of lipid peroxidation, nitric oxide synthase activity, and hydrogen peroxide accumulation. Total glutathione (GSH), mitochondrial GSH, and the activities of major antioxidant enzymes were also lower in the fasted Ppara-null mice. Consequently, the number and extent of nitrated proteins were markedly increased in the fasted Ppara-null mice, although high levels of protein nitration were still detected in the fed Ppara-null mice while many oxidatively modified proteins were only found in the fasted Ppara-null mice. However, the role of inflammation in increased oxidative stress in the fasted Ppara-null mice was minimal based on the similar levels of tumor necrosis factor-alpha change in all groups. These results with increased oxidative stress observed in the fasted Ppara-null mice compared with other groups demonstrate a role for PPAR alpha in fasting-mediated oxidative stress and that inhibition of PPAR alpha functions may increase the susceptibility to oxidative damage in the presence of another toxic agent.
过氧化物酶体增殖物激活受体-α（PPARα）调节脂质稳态，特别是在肝脏中。本研究旨在阐明禁食期间肝脂肪变性与氧化应激之间的关系。禁食的 Ppara 基因敲除小鼠表现出明显的肝脂肪变性，这与脂质过氧化、一氧化氮合酶活性和过氧化氢积累的升高有关。总谷胱甘肽 (GSH)、线粒体 GSH 和主要抗氧化酶的活性在禁食的 Ppara 基因敲除小鼠中也较低。因此，禁食的 Ppara 基因敲除小鼠中硝化蛋白的数量和程度明显增加，尽管在进食的 Ppara 基因敲除小鼠中仍检测到高水平的蛋白硝化，而只有在禁食的 Ppara 基因敲除小鼠中才发现许多氧化修饰的蛋白。然而，根据各组中肿瘤坏死因子-α变化的相似水平，炎症在禁食的 Ppara 基因敲除小鼠中增加氧化应激的作用很小。与其他组相比，在禁食的 Ppara 基因敲除小鼠中观察到的氧化应激增加的这些结果表明 PPARα 在禁食介导的氧化应激中起作用，并且抑制 PPARα 功能可能会增加在存在另一种有毒剂的情况下对氧化损伤的易感性。
