Possible Involvement of Mitochondrial Dysfunction and Oxidative Stress in a Cellular Model of NAFLD Progression Induced by Benzo[a]pyrene/Ethanol CoExposure.
Possible Involvement of Mitochondrial Dysfunction and Oxidative Stress in a Cellular Model of NAFLD Progression Induced by Benzo[a]pyrene/Ethanol CoExposure.
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DOI：
10.1155/2018/4396403
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发表时间：
2018
影响因子：
--
通讯作者：
Fromenty B
中科院分区：
文献类型：
--
作者：
Bucher S;Le Guillou D;Allard J;Pinon G;Begriche K;Tête A;Sergent O;Lagadic-Gossmann D;Fromenty B
暴露于外源性物质可能有利于肥胖患者的非酒精性脂肪肝（NAFL）向非酒精性脂肪性肝炎的转变。最近，我们在不同的NAFL模型中表明，苯并[a]芘（B[a]P）和乙醇共同暴露可诱导脂肪性肝炎样状态。一种模型是用硬脂酸盐和油酸盐孵育2周的HepaRG细胞。在本研究中，我们希望在该模型中确定线粒体功能障碍和活性氧（ROS）过度产生是否可能参与这种脂肪性肝炎样状态的发生。CRISPR/Cas9修饰的细胞也用于指定芳烃受体（AhR）的作用，其被B[a] P有效激活。因此，用B[a]P、乙醇或这两种分子处理非脂肪变性和脂肪变性HepaRG细胞2周。B[a]P/乙醇共暴露降低了脂肪变性HepaRG细胞中线粒体呼吸链活性、线粒体呼吸和线粒体DNA水平，并诱导ROS过度产生。这些有害作用在单独用B[a]P或单独用乙醇处理的脂肪变性细胞和用B[a]P/乙醇处理的非脂肪变性细胞中不太明显或不存在。我们的研究还揭示了B[a]P/乙醇诱导的线粒体呼吸损伤依赖于AhR激活。因此，线粒体功能障碍和ROS产生可以解释暴露于B[a]P和乙醇的脂肪性HepaRG细胞中脂肪性肝炎样状态的发生。
Exposure to xenobiotics could favor the transition of nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis in obese patients. Recently, we showed in different models of NAFL that benzo[a]pyrene (B[a]P) and ethanol coexposure induced a steatohepatitis-like state. One model was HepaRG cells incubated with stearate and oleate for 2 weeks. In the present study, we wished to determine in this model whether mitochondrial dysfunction and reactive oxygen species (ROS) overproduction could be involved in the occurrence of this steatohepatitis-like state. CRISPR/Cas9-modified cells were also used to specify the role of aryl hydrocarbon receptor (AhR), which is potently activated by B[a]P. Thus, nonsteatotic and steatotic HepaRG cells were treated with B[a]P, ethanol, or both molecules for 2 weeks. B[a]P/ethanol coexposure reduced mitochondrial respiratory chain activity, mitochondrial respiration, and mitochondrial DNA levels and induced ROS overproduction in steatotic HepaRG cells. These deleterious effects were less marked or absent in steatotic cells treated with B[a]P alone or ethanol alone and in nonsteatotic cells treated with B[a]P/ethanol. Our study also disclosed that B[a]P/ethanol-induced impairment of mitochondrial respiration was dependent on AhR activation. Hence, mitochondrial dysfunction and ROS generation could explain the occurrence of a steatohepatitis-like state in steatotic HepaRG cells exposed to B[a]P and ethanol.
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DOI：
10.1038/nrendo.2017.42
发表时间：
2017-08
期刊：
Nature reviews. Endocrinology
影响因子：
--
作者：
Foulds CE;Treviño LS;York B;Walker CL
通讯作者：
Walker CL
DOI：
10.1016/j.bpg.2014.07.008
发表时间：
2014-08-01
影响因子：
3.2
作者：
Dietrich, Peter;Hellerbrand, Claus
通讯作者：
Hellerbrand, Claus
影响因子：
3.8
作者：
Bajt, ML;Knight, TR;Jaeschke, H
通讯作者：
Jaeschke, H
影响因子：
13.5
作者：
Garcia-Ruiz, Inmaculada;Rodriguez-Juan, Cristina;Solis-Herruzo, Jose A.
通讯作者：
Solis-Herruzo, Jose A.
DOI：
10.1136/bmj.c1240
发表时间：
2010-03-11
期刊：
BMJ (Clinical research ed.)
影响因子：
--
作者：
Hart CL;Morrison DS;Batty GD;Mitchell RJ;Davey Smith G
通讯作者：
Davey Smith G