Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, and Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China.
Hepatology. 2017 Sep;66(3):809-824. doi: 10.1002/hep.29238. Epub 2017 Jul 20.
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 2α, 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.
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. (Hepatology 2017;66:809-824).
最近的研究表明，脂质诱导的内质网（ER）应激是肝脂肪变性进展的主要原因。胰高血糖素样肽-1 受体激动剂 exenatide（exendin-4）可改善肝脂肪变性，这一点已有越来越多的证据支持。在本研究中，我们通过哺乳动物沉默调节蛋白 1（SIRT1）探讨了 exenatide 是否可以减轻脂质诱导的肝 ER 应激，并阐明了其详细机制。雄性 C57BL/6J 小鼠经高脂肪饮食（HFD）喂养 4 周后，通过腹腔注射给予 exenatide 或生理盐水。我们观察到，HFD 喂养诱导肝 ER 应激，表现为葡萄糖调节蛋白 78、磷酸化蛋白激酶样 ER 激酶和磷酸化真核起始因子 2α 的表达增加，而这些增加被 exenatide 显著抑制。Exenatide 显著降低了 HFD 喂养引起的肝重和肝脂肪变性。一致地，在人 HepG2 细胞和原代鼠肝细胞中，exendin-4 也显著减轻了棕榈酸诱导的 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 介导的去乙酰化增强了热休克因子 1 与热休克蛋白（HSP）基因启动子的结合，从而增加了分子伴侣 HSP70 和 HSP40 的表达，以减轻肝 ER 应激。最后，通过遗传全身杂合子敲除或慢病毒短发夹 RNA 敲低 SIRT1，大大减弱了 exenatide 对去乙酰化热休克因子 1、增加 HSP 表达以及减轻 HFD 喂养小鼠 ER 应激和肝脂肪变性的作用。
SIRT1/热休克因子 1/HSP 途径对于 exenatide 减轻脂质诱导的 ER 应激和肝脂肪变性至关重要，这为支持 exenatide 和肠促胰岛素类似物作为肥胖诱导的肝脂肪变性有希望的治疗药物提供了分子机制证据。（《肝脏病学》2017；66：809-824）。
