Cytochrome P450-2E1 promotes aging-related hepatic steatosis, apoptosis and fibrosis through increased nitroxidative stress.
Cytochrome P450-2E1 promotes aging-related hepatic steatosis, apoptosis and fibrosis through increased nitroxidative stress.
复制标题
细胞色素P450-2E1通过增加的硝基氧化应激促进与衰老相关的肝脂肪变性，凋亡和纤维化。
DOI：
10.1016/j.freeradbiomed.2015.12.016
复制
发表时间：
2016-02
影响因子：
7.4
通讯作者：
Song BJ
中科院分区：
文献类型：
--
作者：
Abdelmegeed MA;Choi Y;Ha SK;Song BJ
乙醇诱导的细胞色素P450-2E1在促进衰老相关性肝病中的作用尚不清楚，因此本研究对其进行了研究。本研究采用青年(7周)和老年雌性(16个月大)野生型(WT)和细胞色素P4502基因缺失的小鼠，研究了肝脏组织学、脂肪变性、细胞凋亡、纤维化和许多氮氧化应激参数随年龄的变化。肝组织学检查显示，与其他组相比，老龄WT组小鼠肝细胞空泡化、气泡性变性和炎细胞浸润明显增加。这些变化伴随着老年WT小鼠肝脏甘油三酯和血清胆固醇显著升高，尽管血清ALT和胰岛素抵抗没有明显改变。老年WT小鼠的肝细胞凋亡率和肝纤维化发生率最高。此外，在老年WT小鼠中观察到肝脏过氧化氢、脂质过氧化、蛋白质羰化、硝化和氧化DNA损伤的水平最高。老年WT小鼠的这些增加伴随着老年WT小鼠线粒体氮氧化应激水平的增加，以及老年WT小鼠线粒体复合体III和IV蛋白的改变，尽管肝脏ATP水平似乎没有变化。一直以来，与衰老相关的亚硝酸氧化变化在老龄的CYP2E1缺失小鼠中非常低。这些结果表明，CYP2E1可能通过增加氮氧化应激而在引起衰老相关的肝脏脂肪变性、细胞凋亡和纤维化中起重要作用，并可能成为预防衰老相关肝病的翻译研究的潜在靶点。
The role of ethanol-inducible cytochrome P450-2E1 (CYP2E1) in promoting aging-dependent hepatic disease is unknown and thus was investigated in this study. Young (7 weeks) and aged female (16 months old) wild-type (WT) and Cyp2e1-null mice were used in this study to evaluate age-dependent changes in liver histology, steatosis, apoptosis, fibrosis and many nitroxidative stress parameters. Liver histology showed that aged WT mice exhibited markedly elevated hepatocyte vacuolation, ballooning degeneration, and inflammatory cell infiltration compared to all other groups. These changes were accompanied with significantly higher hepatic triglyceride and serum cholesterol in aged WT mice although serum ALT and insulin resistance were not significantly altered. Aged WT mice showed the highest rates of hepatocyte apoptosis and hepatic fibrosis. Further, the highest levels of hepatic hydrogen peroxide, lipid peroxidation, protein carbonylation, nitration, and oxidative DNA damage were observed in aged WT mice. These increases in the aged WT mice were accompanied by increased levels of mitochondrial nitroxidative stress and alteration of mitochondrial complex III and IV proteins in aged WT mice, although hepatic ATP levels seems to be unchanged. Consistently, the aging-related nitroxidative changes were very low in aged Cyp2e1-null mice. These results suggest that CYP2E1 is important in causing aging-related hepatic steatosis, apoptosis and fibrosis possibly through increasing nitroxidative stress and that CYP2E1 could be a potential target for translational research in preventing aging-related liver disease.