CuZn-SOD deficiency causes ApoB degradation and induces hepatic lipid accumulation by impaired lipoprotein secretion in mice
CuZn-SOD deficiency causes ApoB degradation and induces hepatic lipid accumulation by impaired lipoprotein secretion in mice
复制标题
DOI：
10.1074/jbc.m603422200
复制
发表时间：
2006-10-20
影响因子：
4.8
通讯作者：
Shirasawa, Takuji
中科院分区：
文献类型：
--
作者：
Uchiyama, Satoshi;Shimizu, Takahiko;Shirasawa, Takuji
肝脏活性氧升高在酒精性肝损伤、丙型肝炎病毒感染和非酒精性脂肪性肝炎等肝脏疾病的发病机制中起重要作用。在本研究中，我们调查和比较肝脏特异性Sod 2（超氧化物歧化酶2）敲除（Sod 2 KO），Sod 1敲除（Sod 1 KO）和Sod 1/肝脏特异性Sod 2双敲除小鼠（双KO）的肝脏脂质代谢。我们观察到脂质过氧化和甘油三酯（TG）的显着增加，在肝脏的Sod 1 KO和双KO小鼠，但不是在肝脏的Sod 2 KO小鼠。我们还发现，高脂肪饮食增强了Sod 1 KO和双KO小鼠的肝脏脂肪变化，但在Sod 2 KO小鼠中没有。这些数据表明，CuZn-SOD缺乏导致肝脏中的脂质积累。为了研究CuZn-SOD缺陷小鼠肝脏脂质蓄积的分子机制，我们使用Triton WR 1339测定了肝脏TG分泌速率。我们发现，在CuZn-SOD缺陷小鼠的TG分泌显着减少。此外，我们观察到载脂蛋白B（apo B）在CuZn-SOD缺陷小鼠的肝脏和血浆中的显著降解，表明apo B的降解损害了肝脏的脂蛋白分泌。我们的数据表明，氧化应激增强肝脏脂质蓄积受损脂蛋白分泌由于在肝脏中的apoB的降解。
Elevated hepatic reactive oxygen species play an important role in pathogenesis of liver diseases, such as alcohol- induced liver injury, hepatitis C virus infection, and nonalcoholic steato-hepatitis. In the present study, we investigated and compared the hepatic lipid metabolisms of liver-specific Sod2 (superoxide dismutase 2) knock-out (Sod2 KO), Sod1 knock-out (Sod1 KO), and Sod1/liver-specific Sod2 double knock- out mice (double KO). We observed significant increases in lipid peroxidation and triglyceride ( TG) in the liver of Sod1 KO and double KO mice but not in the liver of Sod2 KO mice. We also found that high fat diet enhanced fatty changes of the liver in Sod1 KO and double KO mice but not in Sod2 KO mice. These data indicated that CuZn-SOD deficiency caused lipid accumulation in the liver. To investigate the molecular mechanism of hepatic lipid accumulation in CuZn-SOD-deficient mice, we measured TG secretion rate from liver using Triton WR1339. We found significant decrease of TG secretion in CuZn-SOD-deficient mice. Furthermore, we observed marked degradation of apolipoprotein B (apoB) in the liver and plasma of CuZn-SOD-deficient mice, indicating that degradation of apoB impairs secretion of lipoprotein from the liver. Our data suggest that oxidative stress enhances hepatic lipid accumulation by impaired lipoprotein secretion due to the degradation of apoB in liver.