Glucagon-like peptide-1 preserves non-alcoholic fatty liver disease through inhibition of the endoplasmic reticulum stress-associated pathway
Glucagon-like peptide-1 preserves non-alcoholic fatty liver disease through inhibition of the endoplasmic reticulum stress-associated pathway
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DOI：
10.1111/hepr.12551
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发表时间：
2016-04-01
影响因子：
4.2
通讯作者：
Du, Jian
中科院分区：
文献类型：
--
作者：
Ao, Na;Yang, Jing;Du, Jian
胰高血糖素样肽-1 (GLP-1) 因其治疗糖尿病及其有效治疗非酒精性脂肪肝 (NAFLD) 的潜力而得到越来越多的认可。然而，GLP-1 在 NAFLD 中诱导的机制尚不完全清楚。我们研究了 GLP-1 是否可以通过减轻内质网 (ER) 应激来预防 NAFLD。方法给雄性 Sprague-Dawley 大鼠喂食高脂肪饮食，并用长效 GLP-1 受体激动剂利拉鲁肽治疗。研究了内质网应激的生化、形态、遗传和蛋白质表达。在体外，将HepG2细胞暴露于0.4mM棕榈酸酯脂肪酸并用不同浓度的GLP-1处理，并分析ER蛋白46（ERp46）和ER应激通路。在用 ERp46 siRNA 或阴性对照 siRNA 转染后，确定细胞对 ER 应激和细胞凋亡的反应。结果在体内，GLP-1 的治疗减轻了肝脏脂质的积累，减少了炎症并改善了代谢参数。 GLP-1处理显着上调ERp46的表达并下调ER应激标记物。 ER 途径的激活受到 GLP-1 的抑制。在体外也进行了类似的观察。此外，通过 siRNA 介导的沉默抑制 ERp46 表达可增加 ER 应激反应并提高细胞凋亡率。此外，与棕榈酸酯处理后的阴性对照转染细胞相比，GLP-1不能降低转染ERp46 siRNA的细胞的内质网应激和细胞凋亡水平。结论GLP-1通过灭活内质网应激相关的细胞凋亡途径来预防NAFLD。此外，该作用可能与ERp46信号通路有关。
AimGlucagon-like peptide-1 (GLP-1) has been increasingly recognized for treating diabetes mellitus, and for its potential to effectively treat non-alcoholic fatty liver disease (NAFLD). However, the mechanisms of GLP-1 induction in NAFLD are not completely known. We investigated whether GLP-1 can protect against NAFLD by alleviating endoplasmic reticulum (ER) stress.MethodsMale Sprague-Dawley rats were fed a high-fat diet and treated with a long-acting GLP-1 receptor agonist, liraglutide. Biochemical, morphological, genetic and protein expression of ER stress were investigated. In vitro, HepG2 cells were exposed to 0.4mM palmitate fatty acid and treated with different concentrations of GLP-1, and ER protein 46 (ERp46) and ER stress pathways were analyzed. Cellular response to ER stress and apoptosis were determined upon transfection with either ERp46 siRNA or a negative control siRNA.ResultsIn vivo, the treatment of GLP-1 attenuated the hepatic accumulation of lipids, reduced inflammation and improved metabolic parameters. GLP-1 treatment significantly upregulated the expression of ERp46 and downregulated the ER stress marker. Activation of ER pathways was restrained by GLP-1. Similar observations were made in vitro. Furthermore, inhibition of ERp46 expression by siRNA-mediated silencing increased the ER stress response and enhanced cell apoptosis rates. In addition, GLP-1 could not reduce the levels of ER stress and apoptosis in cells transfected with ERp46 siRNA compared with in negative control transfected cells after palmitate treatment.ConclusionGLP-1 protected against NAFLD by inactivating the ER stress-associated apoptosis pathway. In addition, the effect was possibly related to the signaling pathway of ERp46.