Centre for the Study of Liver Diseases, Institute of Internal Medicine, Department of Medical and Occupational Sciences, University of Foggia, Foggia, Italy.
J Pharmacol Exp Ther. 2010 Mar;332(3):922-32. doi: 10.1124/jpet.109.161612. Epub 2009 Dec 11.
Mitochondrial dysfunction and oxidative stress are determinant events in the pathogenesis of nonalcoholic steatohepatitis. Silybin has shown antioxidant, anti-inflammatory, and antifibrotic effects in chronic liver disease. We aimed to study the effect of the silybin-phospholipid complex (SILIPHOS) on liver redox balance and mitochondrial function in a dietary model of nonalcoholic steatohepatitis. To accomplish this, glutathione oxidation, mitochondrial oxygen uptake, proton leak, ATP homeostasis, and H(2)O(2) production rate were evaluated in isolated liver mitochondria from rats fed a methionine- and choline-deficient (MCD) diet and the MCD diet plus SILIPHOS for 7 and 14 weeks. Oxidative proteins, hydroxynonenal (HNE)- and malondialdehyde (MDA)-protein adducts, and mitochondrial membrane lipid composition were also measured. Treatment with SILIPHOS limited glutathione depletion and mitochondrial H(2)O(2) production. Moreover, SILIPHOS preserved mitochondrial bioenergetics and prevented mitochondrial proton leak and ATP reduction. Finally, SILIPHOS limited the formation of HNE- and MDA-protein adducts. In conclusion, SILIPHOS is effective in preventing severe oxidative stress and preserving hepatic mitochondrial bioenergetics in nonalcoholic steatohepatitis induced by the MCD diet. The modifications of mitochondrial membrane fatty acid composition induced by the MCD diet are partially prevented by SILIPHOS, conferring anti-inflammatory and antifibrotic effects. The increased vulnerability of lipid membranes to oxidative damage is limited by SILIPHOS through preserved mitochondrial function.
线粒体功能障碍和氧化应激是非酒精性脂肪性肝炎发病机制中的决定因素。水飞蓟宾具有抗氧化、抗炎和抗纤维化作用，可用于慢性肝病的治疗。我们旨在研究水飞蓟宾磷脂复合物（SILIPHOS）对非酒精性脂肪性肝炎饮食模型中肝脏氧化还原平衡和线粒体功能的影响。为此，我们评估了给予蛋氨酸和胆碱缺乏（MCD）饮食以及 MCD 饮食加 SILIPHOS 7 周和 14 周的大鼠分离肝线粒体的谷胱甘肽氧化、线粒体氧摄取、质子泄漏、ATP 稳态和 H2O2 产生率。还测量了氧化蛋白、4-羟基壬烯醛（HNE）和丙二醛（MDA）-蛋白加合物以及线粒体膜脂质组成。SILIPHOS 处理可限制谷胱甘肽耗竭和线粒体 H2O2 的产生。此外，SILIPHOS 可维持线粒体生物能学并防止线粒体质子泄漏和 ATP 减少。最后，SILIPHOS 可限制 HNE 和 MDA-蛋白加合物的形成。总之，SILIPHOS 可有效预防 MCD 饮食诱导的非酒精性脂肪性肝炎中严重的氧化应激并维持肝线粒体生物能学。MCD 饮食引起的线粒体膜脂肪酸组成的改变部分被 SILIPHOS 预防，从而发挥抗炎和抗纤维化作用。SILIPHOS 通过维持线粒体功能来限制脂质膜对氧化损伤的易感性增加。
