Visualization and isolation of zone-specific murine hepatocytes that maintain distinct cytochrome P450 oxidase expression in primary culture
Visualization and isolation of zone-specific murine hepatocytes that maintain distinct cytochrome P450 oxidase expression in primary culture
复制标题
原代培养物中维持不同细胞色素 P450 氧化酶表达的区域特异性鼠肝细胞的可视化和分离
DOI：
10.1016/j.bbrc.2020.05.202
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发表时间：
2020
影响因子：
3.1
通讯作者：
Inagaki Yutaka
中科院分区：
文献类型：
--
作者：
Kasahara Daigo;Sumiyoshi Hideaki;Endo Hitoshi;Yanagawa Takayo;Nakano Yasuhiro;Matsuki Yuki;Nakao Sachie;Kamiya Akihide;Kimura Hiroshi;Inagaki Yutaka
实质肝细胞负责肝脏的大部分代谢功能，但根据其在肝小叶内的定位表现出不同的功能特性。细胞色素P450氧化酶代表了一个药物代谢酶家族，主要在小叶中心区（3区）的肝细胞中表达。本研究描述了一种独特的转基因小鼠品系，通过EGFP荧光强度区分3区肝细胞和门脉周围1区肝细胞。从这些小鼠中分离的1区和3区肝细胞显示出与体内肝组织相同的区域特异性基因表达模式。肝细胞原代培养实验表明，低氧浓度和Wnt/β-catenin信号的激活可以维持3区特异性P450药物代谢酶的表达，其特征是对对乙酰氨基酚诱导的线粒体功能障碍敏感。这些区域特异性肝细胞为肝脏病理生理学和药物开发的研究领域提供了一个有用的系统。
Parenchymal hepatocytes are responsible for most of the metabolic functions of the liver, but exhibit distinct functional properties depending on their localization within the hepatic lobule. Cytochrome P450 oxidases represent a family of drug-metabolizing enzymes, which are expressed predominantly in hepatocytes localized in the centrilobular area (zone 3). The present study describes a unique transgenic mouse strain that distinguishes zone 3 hepatocytes from periportal zone 1 hepatocytes by the intensity of EGFP fluorescence. Both zone 1 and zone 3 hepatocytes isolated from these mice showed the same zone-specific gene expression patterns as in liver tissuein vivo. Experiments using primary cultures of hepatocytes indicated that a combination of low oxygen concentration and activation of Wnt/β-catenin signaling maintained the expression of zone 3-specific P450 drug-metabolizing enzymes, which was characterized by their susceptibility to acetaminophen-induced mitochondrial dysfunction. These zone-specific hepatocytes provide a useful system in the research area of liver pathophysiology and drug development.