Pigment Epithelium-Derived Factor (PEDF) Prevents Hepatic Fat Storage, Inflammation, and Fibrosis in Dietary Steatohepatitis of Mice
Pigment Epithelium-Derived Factor (PEDF) Prevents Hepatic Fat Storage, Inflammation, and Fibrosis in Dietary Steatohepatitis of Mice
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DOI：
10.1007/s10620-017-4550-x
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发表时间：
2017-04
影响因子：
3.1
通讯作者：
Takafumi Yoshida;J. Akiba;T. Matsui;Kazuo Nakamura;Takao Hisamoto;Mitsuhiko Abe;Yu Ikezono;
中科院分区：
文献类型：
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作者：
Takafumi Yoshida;J. Akiba;T. Matsui;Kazuo Nakamura;Takao Hisamoto;Mitsuhiko Abe;Yu Ikezono;
背景和目的色素上皮衍生因子（PEDF）通过其抗氧化特性已被证明是一种有效的炎症抑制剂。由于氧化反应被认为在非酒精性脂肪性肝炎（NASH）的发生和发展中起关键作用，可以想象PEDF可能对NASH起保护作用。在这项研究中，我们研究了PEDF是否会减缓小鼠模型中NASH的进展。方法小鼠分别饲喂蛋氨酸和胆碱缺乏（MCD）饲粮，同时或不肌肉注射表达腺病毒的PEDF （Ad-PEDF）。对PEDF给药对NASH的影响进行组织学和生化评价。结果Ad-PEDF可显著降低MCD小鼠肝脏脂肪储存和血清ALT水平。双氢乙啶染色显示，与PBS或ad - lacz给药小鼠相比，ad - pedf给药小鼠肝脏中MCD饮食引发的氧化应激减少。Ad-PEDF也能抑制Kupffer细胞的活化和肝纤维化。实时荧光定量pcr结果显示，MCD饮食上调了tnf -α、IL-1β、IL-6、TGF-β、胶原-1和胶原- 3mrna的表达，并在Ad-PEDF的作用下减弱，而MCD饮食诱导的ppar -γmRNA表达下调在Ad-PEDF的作用下恢复。此外，免疫印迹分析显示，MCD饮食诱导的NADPH氧化酶成分上调在ad - pedf给药的小鼠中显著降低。结论本研究结果首次证明PEDF可通过抑制MCD饮食小鼠的脂肪变性和炎症反应来减缓脂肪性肝炎的发生和进展。我们的研究表明，补充PEDF可能是治疗NASH的一种新的治疗策略。
Background and AimsPigment epithelium-derived factor (PEDF) has been shown to be a potent inhibitor of inflammation through its anti-oxidative property. Since oxidative response is considered to play the pivotal role of the development and progression of nonalcoholic steatohepatitis (NASH), it is conceivable that PEDF may play a protective role against NASH. In this study, we examined whether administration of PEDF slowed the progression of NASH in mice models.MethodsMice were fed methionine- and choline-deficient (MCD) diet with or without intramuscular administration of adenovirus-expressing PEDF (Ad-PEDF). Effects of PEDF administration on NASH were histologically and biochemically evaluated.ResultsAdministration of Ad-PEDF significantly decreased hepatic fat storage as well as serum levels of ALT in MCD diet-fed mice. Dihydroethidium staining showed that MCD diet-triggered oxidative stress was reduced in the liver of Ad-PEDF-administered mice compared to that of PBS- or Ad-LacZ-administered mice. Activation of Kupffer cells and hepatic fibrosis was also inhibited by Ad-PEDF administration. Quantitative real-time RT-PCR revealed that MCD diet up-regulated expressions ofTNF-α, IL-1β, IL-6, TGF-β, collagen-1,andcollagen-3mRNA, which were also attenuated with Ad-PEDF administration, whereas MCD diet-induced down-regulation of expressions ofPPAR-γmRNA was restored with Ad-PEDF administration. Furthermore, immunoblotting analysis showed that MCD diet-induced up-regulation of NADPH oxidase components was significantly decreased in Ad-PEDF-administered mice.ConclusionsThe present results demonstrated for the first time that PEDF could slow the development and progression of steatohepatitis through the suppression of steatosis and inflammatory response in MCD diet-fed mice. Our study suggests that PEDF supplementation may be a novel therapeutic strategy for the treatment of NASH.