Ablation of cytochrome P450 omega-hydroxylase 4A14 gene attenuates hepatic steatosis and fibrosis
Ablation of cytochrome P450 omega-hydroxylase 4A14 gene attenuates hepatic steatosis and fibrosis
复制标题
细胞色素 P450 omega-羟化酶 4A14 基因的消除可减轻肝脏脂肪变性和纤维化。
DOI：
10.1073/pnas.1700172114
复制
发表时间：
2017-03-21
影响因子：
11.1
通讯作者：
Guan, Youfei
中科院分区：
文献类型：
--
作者：
Zhang, Xiaoyan;Li, Sha;Guan, Youfei
非酒精性脂肪性肝病（NAFLD）的特征在于单纯性肝脂肪变性（SS）、非酒精性脂肪性肝炎（NASH）、肝纤维化和肝硬化。肝脏中脂肪酸代谢失调在NAFLD的发病机制中起关键作用。细胞色素P450 ω-羟化酶4A 14（CYP 4A 14）是人CYP 4A羟化酶的同源物，在小鼠中催化中链脂肪酸和花生四烯酸的ω-羟化。本研究的目的是确定CYP 4A 14在NAFLD发生和进展中的作用。在这里，我们发现肝脏CYP 4A的表达在NAFLD患者和三种小鼠模型的肝脏中上调。C57 BL/6小鼠肝脏中腺病毒介导的CYP 4A 14过表达导致脂肪肝表型，肝脂肪酸移位酶（FAT/CD 36）表达显著增加。相比之下，喂食高脂饲料或蛋氨酸和胆碱缺乏（MCD）饲料的CYP 4A 14基因缺陷小鼠表现出肝脏脂质蓄积减弱和肝脏FAT/CD 36表达降低。此外，喂食MCD饲料的CYP 4A 14缺陷小鼠的肝脏炎症和纤维化显著改善。总的来说，CYP 4A 14在SS和NASH的发病机制中起重要作用，并且可能代表治疗NAFLD的潜在治疗靶点。
Nonalcoholic fatty liver disease (NAFLD) is characterized by simple hepatic steatosis (SS), nonalcoholic steatohepatitis (NASH), hepatic fibrosis, and cirrhosis. Dysregulated fatty acid metabolism in the liver plays a critical role in the pathogenesis of NAFLD. Cytochrome P450 omega-hydroxylase 4A14 (CYP4A14) is a homolog of human CYP4A hydroxylase that catalyzes omega-hydroxylation ofmediumchain fatty acids and arachidonic acid in mice. The goal of this study was to determine the role of CYP4A14 in the development and the progression of NAFLD. Here, we showed that hepatic CYP4A expression was up-regulated in the livers of patients and three murine models of NAFLD. Adenovirus-mediated overexpression of CYP4A14 in the livers of C57BL/6 mice resulted in a fatty liver phenotype with a significant increase in hepatic fatty acid translocase (FAT/CD36) expression. In contrast, CYP4A14 gene-deficient mice fed a highfat diet or a methionine and choline-deficient (MCD) diet exhibited attenuated liver lipid accumulation and reduced hepatic FAT/CD36 expression. In addition, hepatic inflammation and fibrosis was markedly ameliorated in MCD diet-fed CYP4A14-deficient mice. Collectively, CYP4A14 plays an important role in the pathogenesis of both SS and NASH and may represent a potential therapeutic target for the treatment of NAFLD.