SIRT1/HSF1/HSP Pathway Is Essential for Exenatide-Alleviated, Lipid-Induced Hepatic Endoplasmic Reticulum Stress
SIRT1/HSF1/HSP Pathway Is Essential for Exenatide-Alleviated, Lipid-Induced Hepatic Endoplasmic Reticulum Stress
复制标题
DOI：
10.1002/hep.29238
复制
发表时间：
2017-09-01
期刊：
影响因子：
13.5
通讯作者：
Weng, Jianping
中科院分区：
文献类型：
--
作者：
Zheng, Xiaobin;Xu, Fen;Weng, Jianping
最近的研究表明，脂质诱导的内质网应激是肝脏脂肪变性的主要因素。艾塞那肽（exendin-4）是一种胰高血糖素样肽-1受体激动剂，已知可改善肝脂肪变性，证据越来越多。在本研究中，我们研究了艾塞那肽是否可以通过哺乳动物sirtuin 1 （SIRT1）缓解脂质诱导的肝脏内质网应激，并阐述了其具体机制。饲喂高脂饮食（HFD）的雄性C57BL/6J小鼠腹腔注射艾塞那肽或生理盐水4周。我们观察到，HFD喂养引起肝脏内质网应激，葡萄糖调节蛋白78、磷酸化蛋白激酶样内质网激酶和磷酸化真核起始因子2 α的表达增加，而这些增加被艾塞那肽显著抑制。艾塞那肽显著降低肝脏重量和HFD致肝脂肪变性。同样，在人HepG2细胞和小鼠原代肝细胞中，exendin-4也能显著缓解棕榈酸盐诱导的内质网应激和脂质积累。重要的是，进一步的研究表明，exendin-4通过sirt1介导的去乙酰化，增强热休克因子1与热休克蛋白（HSP）基因启动子的结合，从而增加分子伴侣蛋白HSP70和HSP40的表达，从而缓解肝脏内质网应激。最后，通过基因整体杂合敲除或慢病毒短发夹RNA敲除对SIRT1的抑制，大大降低了艾塞那肽对热休克因子1去乙酰化的作用，增加了HSP的表达，减轻了内质网应激和肝脏脂肪变性。结论：SIRT1/热休克因子1/HSP通路在艾塞那肽缓解、脂质诱导的内质网应激和肝脂肪变性中起重要作用，这为支持艾塞那肽和肠促胰岛素模拟物作为治疗肥胖诱导的肝脂肪变性的分子机制提供了证据。
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.