氧化损伤与内质网应激在四氯化碳致大鼠肝脂肪变性中的作用机制

Oxidative Damage and ER Stress are Implicated in CCl_4-induced SD Rat Hepatic Steatosis

肝脂肪变性是长期饮酒、肥胖、药物中毒等致脂肪肝形成过程中重要的中间阶段,严重的脂肪堆积会导致肝细胞坏死或肝硬化,但是有关肝脂肪变性的分子机理目前仍不十分清楚.本实验利用四氯化碳建立大鼠肝脂肪变性模型,四氯化碳处理组较对照组肝脏丙二醛含量增加68%,内质网应激标志蛋白GRP78mRNA水平和蛋白质水平表达均明显增加;人肝癌细胞株HepG2体外培养中,加入四氯化碳处理后内质网发生应激,并导致SREBP1表达增加且活化.结果表明,四氯化碳导致的肝脂肪变性与肝细胞的氧化损伤和内质网应激有关,其分子机理可能为内质网应激发生后促进SREBP1转录因子的表达与活化,SREBP1在细胞核内参与生脂相关酶如HMGCoA还原酶等基因的诱导表达,生脂相关酶含量的增加进一步使肝细胞甘油三酯、胆固醇合成增加,脂质的异常堆积导致了肝脂肪变性的发生.

Hepatic steatosis, featured in hepatic accumulation in lipid, has been recognized as a promising stage toward to fatty liver, initiated by such as chronic alcoholism, obesity or certain drug intoxication and etc., and finally leads to hepatic necrosis and cirrhosis. However, the underlying mechanism on the hepatic steatosis is poorly understood. Hepatic steatosis rats were induced by subcutaneous injections of carbon tetrachloride （CCl4） solution. The product increase of hepatic malonaldehyde was 68%, and higher level of GRP78 expression was found by RT-PCR and Western blot in the liver of rats treated by CCl4. Further study using cultured HepG2 cells showed that CCl4 could lead to endoplasmic reticulum stress （ERS）, which induced the expression and activation of sterol regulatory element binding protein-1 （SREBP-1）. The results suggest that oxidative damage and endoplasmic reticulum stress are implicated in the CCl4 induced hepatic steatosis. This ERS disburdened by CCl4 in turn leads to translocation and binding of SREBP-1 to those promoter regions of lipogenic genes, which is assumed to enhance those lipogenic gene transcriptions responsible for triglyceride/cholesterol biosynthesis and accumulation.