Protective role of biliverdin against bile acid-induced oxidative stress in liver cells
Protective role of biliverdin against bile acid-induced oxidative stress in liver cells
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DOI：
10.1016/j.freeradbiomed.2016.06.016
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发表时间：
2016-08-01
影响因子：
7.4
通讯作者：
Marin, Jose J. G.
中科院分区：
文献类型：
--
作者：
Gonzalez-Sanchez, Ester;Perez, Maria J.;Marin, Jose J. G.
胆汁酸的积累影响线粒体，引起氧化应激。抗氧化防御被认为包括通过BV还原酶α（BVR α）将胆绿素（BV）生物转化为胆红素（BR）。BLVRA中的突变（c.214C > A）导致无功能酶（mutBVR α）。因此，患有胆汁淤积的纯合子携带者发展为绿色黄疸。BVR α缺乏是否会降低BV依赖的胆汁酸保护作用是一个相关问题，因为在格陵兰岛311名个体中筛选mut-BLVRA等位基因（a）显示，该SNP在研究的因纽特人中相对频繁（1% a/a和4.5% Lambda/a）。在三种人肝细胞系中，发现BVR α表达（HepG 2>亚历山大> HuH-7）与基础活性氧（ROS）水平之间呈负相关，然而，BV降低脱氧胆酸（DCA）或重铬酸钾（PDC）诱导的氧化应激和细胞死亡的能力在这些细胞中相似。在人胎盘JAr细胞中转导BVR α或mutBVR α，BVR α表达可忽略不计，或在肝细胞中沉默内源性BVR α表达，对DCA诱导的氧化应激和细胞死亡或BV介导的细胞保护作用没有影响。DCA刺激超氧阴离子和过氧化氢的产生，而BV只抑制后者。DCA和其他二羟基胆汁酸，而不是PDC，通过FXR非依赖性和BV不敏感机制诱导肝细胞中BVR α和血红素加氧酶-1（HO-1）的上调。总之，BV发挥直接和BVR α独立的抗氧化和细胞保护作用，而胆汁淤积中胆汁酸的积累刺激有利于血红素生物转化为BV和BR的酶的表达。(C)2016爱思唯尔B. V.保留所有权利。
The accumulation of bile acids affects mitochondria causing oxidative stress. Antioxidant defense is accepted to include biotransformation of biliverdin (BV) into bilirubin (BR) through BV reductase alpha (BVR alpha). The mutation (c.214C > A) in BLVRA results in a non-functional enzyme (mutBVR alpha). Consequently, homozygous carriers suffering from cholestasis develop green jaundice. Whether BVR alpha deficiency reduces BV-dependent protection against bile acids is a relevant question because a screening of the mut-BLVRA allele (a) in 311 individuals in Greenland revealed that this SNP was relatively frequent in the Inuit population studied (1% a/a and 4.5% Lambda/a). In three human liver cell lines an inverse correlation between BVR alpha expression (HepG2 > Alexander > HuH-7) and basal reactive oxygen species (ROS) levels was found, however the ability of BV to reduce oxidative stress and cell death induced by deoxycholic acid (DCA) or potassium dichromate (PDC) was similar in these cells. The transduction of BVR alpha or mutBVR alpha in human placenta JAr cells with negligible BVR alpha expression or the silencing of endogenous BVR alpha expression in liver cells had no effect on DCA-induced oxidative stress and cell death or BV-mediated cytoprotection. DCA stimulated both superoxide anion and hydrogen peroxide production, whereas BV only inhibited the latter. DCA and other dihydroxy-bile acids, but not PDC, induced up-regulation of both BVR alpha and heme oxygenase-1 (HO-1) in liver cells through a FXR independent and BV insensitive mechanism. In conclusion, BV exerts direct and BVR alpha-independent antioxidant and cytoprotective effects, whereas bile acid accumulation in cholestasis stimulates the expression of enzymes favoring the heme biotransformation into BV and BR. (C) 2016 Elsevier B.V. All rights reserved.