药理学抑制 NOX4 可通过改善氧化应激和线粒体功能来减轻小鼠的酒精性肝损伤。
Pharmacological inhibition of NOX4 ameliorates alcohol-induced liver injury in mice through improving oxidative stress and mitochondrial function.
机构信息
Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA; Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA.
Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA.
出版信息
Biochim Biophys Acta Gen Subj. 2017 Jan;1861(1 Pt A):2912-2921. doi: 10.1016/j.bbagen.2016.09.009. Epub 2016 Sep 12.
BACKGROUND
Oxidative stress plays a crucial role in the development of alcoholic liver disease (ALD), however effective pharmacological treatment for oxidative injury is still lacking. The objective of this study was to determine whether inhibition of NADPH oxidase activity could reverse alcohol-induced liver injury via protecting mitochondrial functions.
METHODS
C57BL/6J mice were pair-fed with Lieber-DeCarli control or ethanol diet for four week with or without administration with 30mg/kg/d GKT137831, a NOX4 inhibitor for the last two weeks. H4IIEC3 cells were transfected with scrambled or NOX4 shRNA. Cells were then treated with 200mM ethanol for 48h.
RESULTS
Alcohol exposure induced NOX4 expression in the liver and mitochondrial fraction. GKT137831 partially reversed alcohol-induced liver injury and elevation of serum HO. The levels of mitochondrial ROS, mitochondrial DNA, respiratory chain complex IV, and hepatic ATP were partially reversed by GKT137831 after alcohol exposure. Furthermore GKT137831 ameliorated alcohol-induced lipid accumulation and increased HNF-4α and β-oxidation enzymes. GKT137831 also decreased alcohol-induced apoptosis coupled with decreased insertion of Bax into mitochondria and decreased activation of cleaved caspase-9 and cleaved PARP. Mechanistic study shows that ethanol induced expression of NOX4 in H4IIEC3 cells. Knockdown of NOX4 caused an increased mitochondrial membrane potential, decreased mitochondrial superoxide levels, reduced number of apoptotic cells, decreased lipid accumulation, and improved ATP levels and NAD+/NADH ratio after ethanol treatment.
CONCLUSION
Pharmacological inhibition of NOX4 activity protects against alcohol-induced fat accumulation and activation of intrinsic apoptosis via improving mitochondrial function.
GENERAL SIGNIFICANCE
Pharmacological inhibition of NOX4 could be a promising treatment for ALD.
背景
氧化应激在酒精性肝病（ALD）的发展中起着至关重要的作用，然而，针对氧化损伤的有效药物治疗仍然缺乏。本研究旨在确定抑制 NADPH 氧化酶活性是否可以通过保护线粒体功能来逆转酒精引起的肝损伤。
方法
用 Lieber-DeCarli 对照或乙醇饮食喂养 C57BL/6J 小鼠 4 周，并在最后 2 周给予 30mg/kg/d 的 GKT137831（NOX4 抑制剂）。将 H4IIEC3 细胞用 scrambled 或 NOX4 shRNA 转染。然后用 200mM 乙醇处理细胞 48h。
结果
酒精暴露诱导肝脏和线粒体部分的 NOX4 表达。GKT137831 部分逆转了酒精引起的肝损伤和血清 HO 的升高。GKT137831 部分逆转了酒精暴露后线粒体 ROS、线粒体 DNA、呼吸链复合物 IV 和肝 ATP 的水平。此外，GKT137831 改善了酒精引起的脂质积累，并增加了 HNF-4α 和β氧化酶。GKT137831 还减少了酒精诱导的凋亡，同时减少了 Bax 插入线粒体和激活 cleaved caspase-9 和 cleaved PARP。机制研究表明，乙醇诱导了 H4IIEC3 细胞中 NOX4 的表达。NOX4 的敲低导致线粒体膜电位增加，线粒体超氧化物水平降低，凋亡细胞数量减少，脂质积累减少，乙醇处理后 ATP 水平和 NAD+/NADH 比值提高。
结论
NOX4 活性的药物抑制通过改善线粒体功能，防止酒精引起的脂肪堆积和内在凋亡的激活。
一般意义
NOX4 的药物抑制可能是治疗 ALD 的一种有前途的方法。
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