Nonalcoholic fatty liver disease impairs the cytochrome P-450-dependent metabolism of α-tocopherol (vitamin E)
Nonalcoholic fatty liver disease impairs the cytochrome P-450-dependent metabolism of α-tocopherol (vitamin E)
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DOI：
10.1016/j.jnutbio.2017.06.003
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发表时间：
2017-09-01
影响因子：
5.6
通讯作者：
Galli, Francesco
中科院分区：
文献类型：
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作者：
Bartolini, Desiree;Torquato, Pierangelo;Galli, Francesco
本研究旨在研究非酒精性脂肪性肝病 (NAFLD) 的体内和体外模型中α-生育酚（维生素 E）的酶促代谢及其与在肝脏脂质代谢和解毒中发挥关键作用的维生素 E 反应基因的关系。实验模型包括喂食加或不加果糖的高脂肪饮食的小鼠 (HFD+F) 以及用脂肪生成剂棕榈酸酯、油酸酯或果糖处理的 HepG2 人肝癌细胞。 CYP4F2 蛋白（一种细胞色素 P-450 亚型，具有 α-生育酚 omega-羟化酶活性）在 HFD 中降低，在 HFD+F 小鼠肝脏中降低得更多；这一发现与肝脏中α-生育酚水平升高以及相应长链代谢物α-13-羟基和α-13-羧基苯并二氢吡喃醇的形成减少有关。还观察到 PPAR-γ 和 SREBP-1 蛋白的表达降低，这两种维生素 E 反应基因在脂质代谢和 CYP4F2 基因调节中发挥关键作用。在暴露于脂肪生成剂和细胞毒性剂棕榈酸水平升高的过程中，在 HepG2 细胞中观察到 CYP4F2 基因短暂激活，随后出现抑制反应。这种基因抑制效应通过油酸和 α-生育酚的共同处理而进一步加剧，并且在 PPAR-γ 以及 SREBP 亚型 1 和 2 中也观察到。这种基因反应与 α-生育酚的摄取增加和 omega-羟基化有关，这表明 CYP4F2 在维生素 E 的酶促代谢中的次要作用 在 HepG2 细胞中。总之，实验性 NAFLD 中 α-生育酚的肝脏代谢和基因反应受到损害。 (C) 2017 年，爱思唯尔公司出版
This study aims to investigate in in vivo and in vitro models of nonalcoholic fatty liver disease (NAFLD) the enzymatic metabolism of alpha-tocopherol (vitamin E) and its relationship to vitamin E-responsive genes with key role in the lipid metabolism and detoxification of the liver. The experimental models included mice fed a high-fat diet combined or not with fructose (HFD+F) and HepG2 human hepatocarcinoma cells treated with the lipogenic agents palmitate, oleate or fructose. CYP4F2 protein, a cytochrome P-450 isoform with proposed alpha-tocopherol omega-hydroxylase activity, decreased in HFD and even more in HFD+F mice liver; this finding was associated with increased hepatic levels of alpha-tocopherol and decreased formation of the corresponding long-chain metabolites alpha-13-hydroxy and alpha-13-carboxy chromanols. A decreased expression was also observed for PPAR-gamma and SREBP-1 proteins, two vitamin E-responsive genes with key role in lipid metabolism and CYP4F2 gene regulation. A transient activation of CYP4F2 gene followed by a repression response was observed in HepG2 cells during the exposure to increasing levels of the lipogenic and cytotoxic agent palmitic acid; such gene repression effect was further exacerbated by the co-treatment with oleic acid and alpha-tocopherol and was also observed for PPAR-gamma and the SREBP isoforms 1 and 2. Such gene response was associated with increased uptake and omega-hydroxylation of alpha-tocopherol, which suggests a minor role of CYP4F2 in the enzymatic metabolism of vitamin E in HepG2 cells. In conclusion, the liver metabolism and gene response of alpha-tocopherol are impaired in experimental NAFLD. (C) 2017 Published by Elsevier Inc.