Adropin protects against liver injury in nonalcoholic steatohepatitis via the Nrf2 mediated antioxidant capacity
Adropin protects against liver injury in nonalcoholic steatohepatitis via the Nrf2 mediated antioxidant capacity
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Adropin 通过 Nrf2 介导的抗氧化能力防止非酒精性脂肪性肝炎的肝损伤
DOI：
10.1016/j.redox.2018.101068
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发表时间：
2019-02-01
期刊：
影响因子：
11.4
通讯作者：
Ling, Wenhua
中科院分区：
文献类型：
--
作者：
Chen, Xu;Xue, Hongliang;Ling, Wenhua
阿德平是一种分泌信号肽，在改善血糖稳态和血脂异常方面显示出良好的作用。然而，这种多肽是否影响非酒精性脂肪性肝炎(NASH)仍不清楚。本研究测定了饮食诱导的NASH小鼠的血清肾上腺素水平、肝损伤和氧化应激。采用阿托品基因敲除小鼠和棕榈酸酯处理的原代肝细胞，观察阿托品对肝损伤的影响。结果表明，NASH小鼠血清肾上腺素水平降低，且与肝损伤程度呈负相关。敲除肾上腺素显著加剧了蛋氨酸-胆碱缺乏饮食(MCD)或西方饮食(WD)喂养小鼠的肝脏脂肪变性、炎症反应和纤维化。阿托品生物活性多肽的治疗改善了小鼠的NASH进展。Adropin通过上调GCLC、Gclm和GPX1的表达，依赖于Nrf2的转录活性，并通过增加谷胱甘肽(GSH)水平来减轻肝细胞损伤。肾上腺素可显著增加CBP的表达并促进其与Nrf2的结合，从而增强Nrf2的转录活性。此外，AAV8介导的肝脏Nrf2表达过表达在功能上恢复了肾上腺素缺乏MCD喂养的小鼠的肝损伤。这些发现为肾上腺素激活Nrf2信号通路在NASH肝损伤中发挥保护作用提供了证据，因此可能成为防治NASH的新靶点。
Adropin, a secretory signal peptide, has shown beneficial effects on improving glucose homeostasis and dyslipidemia. However, whether this peptide affects nonalcoholic steatohepatitis (NASH) has remained unclear. In this study, the serum adropin levels, liver injury and oxidative stress were measured in diet-induced NASH mice. Adropin knock-out mice and palmitate treated primary hepatic cells were used to investigate the influence of adropin on liver injury. Our results show that serum adropin levels were decreased and negatively correlated with liver injury in NASH mice. Knockout of adropin significantly exacerbated hepatic steatosis, inflammatory responses and fibrosis in mice after either methionine-choline deficient diet (MCD) or western diet (WD) feeding. And the treatment with adropin bioactive peptides ameliorated NASH progression in mice. Adropin alleviated hepatocyte injury by upregulating the expression of Gclc, Gclm, and Gpx1 in a manner dependent on Nrf2 transcriptional activity and by increasing the glutathione (GSH) levels. And adropin significantly increased CBP expression and promoted its binding with Nrf2, which enhanced Nrf2 transcriptional activity. Furthermore, AAV8-mediated overexpression of hepatic Nrf2 expression functionally restored the liver injury induced by adropin-deficiency MCD-fed mice. These findings provide evidence that adropin activates Nrf2 signaling and plays a protective role in liver injury of NASH and therefore might represent a novel target for the prevention and treatment of NASH.