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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >SIRT1/HSF1/HSP Pathway Is Essential for Exenatide-Alleviated, Lipid-Induced Hepatic Endoplasmic Reticulum Stress
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SIRT1/HSF1/HSP Pathway Is Essential for Exenatide-Alleviated, Lipid-Induced Hepatic Endoplasmic Reticulum Stress

机译：SIRT1 / HSF1 / HSP途径对于卓然肽缓解，脂质诱导的肝内质网胁迫是必不可少的

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Recent studies have indicated that lipid-induced endoplasmic reticulum (ER) stress is a major contributor to the progression of hepatic steatosis. Exenatide (exendin-4), a glucagon-like peptide-1 receptor agonist, is known to improve hepatic steatosis, with accumulating evidence. In this study, we investigated whether exenatide could alleviate lipid-induced hepatic ER stress through mammal sirtuin 1 (SIRT1) and illustrated the detailed mechanisms. Male C57BL/6J mice challenged with a high-fat diet (HFD) were treated with exenatide or normal saline by intraperitoneal injection for 4 weeks. We observed that HFD feeding induced hepatic ER stress as indicated by increased expression of glucose-regulated protein 78, phosphorylated protein kinase-like ER kinase, and phosphorylated eukaryotic initiation factor 2 alpha, while these increases were significantly inhibited by exenatide. Exenatide notably decreased the liver weight and hepatic steatosis induced by HFD challenge. Consistently, in human HepG2 cells and primary murine hepatocytes, exendin-4 also significantly alleviated the ER stress and lipid accumulation induced by palmitate. Importantly, further studies showed that exendin-4 enhanced the binding of heat shock factor 1 to the promoter of heat shock protein (HSP) genes through SIRT1-mediated deacetylation, which then increased the expression of molecular chaperones HSP70 and HSP40 to alleviate hepatic ER stress. Finally, inhibition of SIRT1 by genetic whole-body heterozygous knockout or by lentiviral short hairpin RNA knockdown greatly diminished the effect of exenatide on deacetylating heat shock factor 1, increasing HSP expression and alleviating ER stress and hepatic steatosis in HFD-fed mice. Conclusion: The SIRT1/heat shock factor 1/HSP pathway is essential for exenatide-alleviated, lipid-induced ER stress and hepatic steatosis, which provides evidence for a molecular mechanism to support exenatide and incretin mimetics as promising therapeutics for obesity-induced hepatic steatosis.
机译：最近的研究表明，脂质诱导的内质网（ER）应力是肝脏脂肪变性进展的主要因素。 exenatide（Exendin-4），葡萄糖素样肽-1受体激动剂，已知改善肝脏脂肪变性，积累证据。在这项研究中，我们研究了exenatide是否可以通过哺乳动物Sirtuin 1（SIRT1）来缓解脂质诱导的肝脏ER应力，并说明了详细的机制。用高脂饮食（HFD）挑战的雄性C57BL / 6J小鼠通过腹腔注射治疗4周，用exenatide或生理盐水处理。我们观察到HFD喂养诱导肝脏ER应力，如通过葡萄糖调节蛋白质78，磷酸化蛋白激酶样ER激酶和磷酸化的真核激酶2α表达，而这些增加由eXenatide显着抑制。艾烯酰胺显着降低了HFD攻击诱导的肝脏重量和肝脏脂肪变性。一致地，在人HepG2细胞和原发生鼠肝细胞中，Exendin-4也显着减轻了棕榈酸酯诱导的ER应激和脂质积累。重要的是，进一步的研究表明，Exendin-4通过SIRT1介导的脱乙酰化增强了热休克因子1与热休克蛋白（HSP）基因的启动子的结合，然后增加了分子伴侣Hsp70和Hsp40的表达，以缓解肝脏ER应激。最后，抑制SIRT1通过遗传全身杂合子敲除或通过慢病毒短发夹RNA敲低大大减少了艾塞司脂酰胺在脱乙酰末乙酰末热休克因子1上的作用，增加了HSP表达和缓解HFD-FED小鼠中的ER应激和肝脏脂肪变性。结论：SIRT1 /热休克因子1 / HSP途径对于卓然肽缓解，脂质诱导的ER应激和肝脏脂肪变性至关重要，这提供了一种支持exenatide和Incetin模拟物作为肥胖诱导的肝脏脂肪变性的有前途治疗方法的分子机制的证据。

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