Serotonin mediates oxidative stress and mitochondrial toxicity in a murine model of nonalcoholic steatohepatitis
Serotonin mediates oxidative stress and mitochondrial toxicity in a murine model of nonalcoholic steatohepatitis
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DOI：
10.1053/j.gastro.2007.05.019
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发表时间：
2007-08-01
期刊：
影响因子：
29.4
通讯作者：
Clavien, Pierre-Alain
中科院分区：
文献类型：
--
作者：
Nocito, Antonio;Dahm, Felix;Clavien, Pierre-Alain
背景与目的：非酒精性脂肪性肝炎（NASH）是西方最常见的肝酶升高的原因之一。它的流行率可能会进一步增加，与代谢综合征的流行增加平行。近年来，单胺氧化酶A（MAO-A）降解5-羟色胺被认为是活性氧的重要来源。因此，我们在饮食诱导的脂肪性肝炎小鼠模型中检测了5-羟色胺的致病作用。方法：用胆碱-蛋氨酸缺乏饲料喂养野生型和色氨酸羟化酶1（Tph 1（-/-））缺陷型小鼠2周和6周。氯吉林可抑制MAO-A。通过组织学、免疫组化和生化分析评估脂肪变性、肝细胞损伤和肝脏炎症。逆转录聚合酶链反应和Western blot分析MAO-A和5-羟色胺转运蛋白的表达水平。通过测定脂质过氧化反应检测氧化应激。线粒体损伤通过电子显微镜和细胞色素c释放定量测定。结果如下：在胆碱-蛋氨酸缺乏饮食后，Tph 1（-/-）小鼠显示出同等程度的脂肪变性，但肝细胞损伤减少，炎症不太严重。这些NASH定义特征的差异可归因于5-羟色胺的摄取和催化增加，产生活性氧和脂质过氧化物水平的提高，其通过线粒体损伤和炎症介导肝细胞损伤。MAO-A的抑制减少了野生型小鼠的肝细胞损伤。相应地，MAO-A表达在人NASH中显著上调。结论：这项研究提供了证据表明，5-羟色胺在脂肪性肝炎的发病机制中起作用，因此可能代表预防和治疗NASH的新靶点。
Background & Aims: Nonalcoholic steatohepatitis (NASH) is one of the most common causes of liver enzyme elevation in the West. Its prevalence is likely to increase further, paralleling the epidemic increase of the metabolic syndrome. Serotonin degradation by monoamine oxidase A (MAO-A) was recently implicated as an important source of reactive oxygen species. We therefore tested the pathogenetic role of serotonin in a murine model of diet-induced steatohepatitis. Methods: Wild-type and serotonin-deficient mice, tryptophan hydroxylase 1 (Tph1(-/-)) were fed a choline-methionine-deficient diet for 2 and 6 weeks. MAO-A was inhibited with clorgyline. Steatosis, hepatocyte injury, and hepatic inflammation were assessed by histology, immunohistochemistry, and biochemical analysis. Expression levels of MAO-A and serotonin transporter were analyzed by reverse-transcription polymerase chain reaction and Western blot. Oxidative stress was detected by measuring lipid peroxidation. Mitochondrial damage was determined by electron microscopy and quantification of cytochrome c release. Results: After choline-methionine-deficient diet, Tph1(-/-) mice displayed an equal degree of steatosis, yet reduced hepatocellular injury and less severe inflammation. The difference in these NASH-defining features could be attributed to, an increased uptake and catabolism of serotonin, yielding enhanced levels of reactive oxygen species and lipid peroxides, which mediated hepatocellular injury by mitochondrial damage and inflammation. Inhibition of MAO-A reduced hepatocellular damage in wild-type mice. Correspondingly, MAO-A expression was up-regulated significantly in human NASH. Conclusions: This study provides evidence that serotonin plays a role in the pathogenesis of steatohepatitis, and therefore might represent a novel target for the prevention and treatment of NASH.