Department of Pharmacology and Institute of Cardiovascular Research, School of Medicine, Chonbuk National University, Jeonju, Chonbuk, Republic of Korea.
Int J Biochem Cell Biol. 2011 Oct;43(10):1469-82. doi: 10.1016/j.biocel.2011.06.010. Epub 2011 Jun 22.
The role of ER stress on hepatic steatosis was investigated in a rat model. We injected CCl(4) into rats and found that CCl(4) could induce hepatic lipid accumulation, confirmed by Oil Red O staining and by measurement of triglyceride and cholesterol. The expression of ApoB, an apolipoprotein, was decreased in plasma and increased in the liver of CCl(4)-treated animals. The ER stress response was also significantly increased by CCl(4). P450 2E1 expression and activity were increased through interactions of P450 2E1 with NADPH-dependent P450 reductase (NPR) under CCl(4)-treated conditions. In HepG2 cells, intracellular lipid accumulation and its signaling were comparable to in vivo results. In order to elucidate the effect of the ER stress response itself, tunicamycin, an N-acetyl-glycosylation inhibitor, was injected into rats, followed by Oil Red O staining, lipid/triglyceride/cholesterol accumulation analysis, and examination of ApoB expression. Additionally, the ER stress response and upregulation of P450 2E1 were also confirmed in the tunicamycin-treated rats. All of the responses were similar to those seen with CCl(4). The P450 2E1 inhibitor diallyl sulphide (DAS), N-acetylcysteine (NAC), and reduced glutathione (GSH) antioxidants also regulated processes, including ApoB expression and lipid accumulation in CCl(4)-treated animals. In the presence of tunicamycin, DAS or NAC/GSH regulated all of the pathological phenomena with the exception of the ER stress response. In summary, CCl(4) induces liver steatosis, a process involving ER stress-induced P450 2E1 activation and ROS production.
我们在大鼠模型中研究了内质网应激（ER stress）在肝脂肪变性中的作用。我们向大鼠注射 CCl4，发现 CCl4 可以诱导肝内脂质积累，这可以通过油红 O 染色和甘油三酯及胆固醇的测量来证实。apoB，一种载脂蛋白，在血浆中的表达降低，而在 CCl4 处理的动物肝脏中表达增加。CCl4 还显著增加了 ER 应激反应。在 CCl4 处理条件下，P450 2E1 通过与 NADPH 依赖性 P450 还原酶（NPR）相互作用而表达和活性增加。在 HepG2 细胞中，细胞内脂质积累及其信号与体内结果相当。为了阐明 ER 应激反应本身的影响，我们向大鼠注射了衣霉素（一种 N-乙酰糖基化抑制剂），然后进行油红 O 染色、脂质/甘油三酯/胆固醇积累分析以及 apoB 表达检测。此外，还在衣霉素处理的大鼠中证实了 ER 应激反应和 P450 2E1 的上调。所有的反应都与 CCl4 相似。P450 2E1 抑制剂二烯丙基二硫（DAS）、N-乙酰半胱氨酸（NAC）和还原型谷胱甘肽（GSH）抗氧化剂也调节了包括 apoB 表达和 CCl4 处理动物脂质积累在内的过程。在衣霉素存在的情况下，DAS 或 NAC/GSH 调节了除 ER 应激反应之外的所有病理现象。总之，CCl4 诱导肝脂肪变性，这一过程涉及 ER 应激诱导的 P450 2E1 激活和 ROS 产生。
