Department of Internal Medicine, University of Catania, Catania, Italy.
Transl Res. 2012 Jun;159(6):477-86. doi: 10.1016/j.trsl.2011.12.003. Epub 2012 Jan 2.
Nonalcoholic steatohepatitis (NASH) is associated with increased liver-related mortality. Disturbances in hepatic lipid homeostasis trigger oxidative stress and inflammation (ie, lipotoxicity), leading to the progression of NASH. This study aimed at identifying whether silibinin may influence the molecular events of lipotoxicity in a mouse model of NASH. Eight-week-old db/db mice were fed a methionine-choline deficient (MCD) diet for 4 weeks and treated daily with silibinin (20 mg/kg intraperitoneally) or vehicle. Liver expression and enzyme activity of stearoyl-CoA desaturase-1 and acyl-CoA oxidase, and expression of liver fatty acid-binding protein were assessed. Hepatic levels of reactive oxygen species, thiobarbituric acid-reactive substances (TBARS), 3-nitrotyrosine (3-NT), inducible nitric oxide synthase (iNOS), and nuclear factor kappa B (NFkB) activities were also determined. Silibinin administration decreased serum alanine aminotransferase and improved liver steatosis, hepatocyte ballooning, and lobular inflammation in db/db mice fed an MCD diet. Gene expression and activity of stearoyl-CoA desaturase-1 were reduced in db/db mice fed an MCD diet compared with lean controls and were increased by silibinin; moreover, silibinin treatment induced the expression and activity of acyl-CoA oxidase and the expression of liver fatty acid-binding protein. Vehicle-treated animals displayed increased hepatic levels of reactive oxygen species and TBARS, 3-NT staining, and iNOS expression; silibinin treatment markedly decreased reactive oxygen species and TBARS and restored 3-NT and iNOS to the levels of control mice. db/db mice fed an MCD diet consistently had increased NFkB p65 and p50 binding activity; silibinin administration significantly decreased the activity of both subunits. Silibinin treatment counteracts the progression of liver injury by modulating lipid homeostasis and suppressing oxidative stress-mediated lipotoxicity and NFkB activation in experimental NASH.
非酒精性脂肪性肝炎（NASH）与肝相关死亡率增加有关。肝内脂质稳态的紊乱会引发氧化应激和炎症（即脂毒性），导致 NASH 的进展。本研究旨在确定水飞蓟素是否会影响 NASH 小鼠模型中脂毒性的分子事件。将 8 周龄 db/db 小鼠用蛋氨酸-胆碱缺乏（MCD）饮食喂养 4 周，并每天用水飞蓟素（20mg/kg 腹腔内注射）或载体处理。评估肝内硬脂酰辅酶 A 去饱和酶-1 和酰基辅酶 A 氧化酶的表达和酶活性，以及肝脂肪酸结合蛋白的表达。还测定了肝内活性氧、硫代巴比妥酸反应物质（TBARS）、3-硝基酪氨酸（3-NT）、诱导型一氧化氮合酶（iNOS）和核因子 kappa B（NFkB）活性。水飞蓟素给药降低了血清丙氨酸氨基转移酶，并改善了 db/db 小鼠 MCD 饮食喂养引起的肝脂肪变性、肝细胞气球样变和肝小叶炎症。与瘦对照组相比，db/db 小鼠 MCD 饮食喂养时硬脂酰辅酶 A 去饱和酶-1 的基因表达和活性降低，而水飞蓟素可增加其表达和活性；此外，水飞蓟素治疗诱导酰基辅酶 A 氧化酶的表达和活性以及肝脂肪酸结合蛋白的表达。载体处理的动物显示肝内活性氧和 TBARS、3-NT 染色和 iNOS 表达增加；水飞蓟素治疗显著降低了活性氧和 TBARS，并将 3-NT 和 iNOS 恢复到对照小鼠的水平。db/db 小鼠 MCD 饮食喂养时持续存在 NFkB p65 和 p50 结合活性增加；水飞蓟素给药显著降低了两个亚基的活性。水飞蓟素治疗通过调节脂质稳态和抑制氧化应激介导的脂毒性和 NFkB 激活来抑制实验性 NASH 中的肝损伤进展。
