Fibroblast growth factor 21 is induced by endoplasmic reticulum stress
Fibroblast growth factor 21 is induced by endoplasmic reticulum stress
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DOI：
10.1016/j.biochi.2012.10.019
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发表时间：
2013-04-01
期刊：
影响因子：
3.9
通讯作者：
Gaemers, Ingrid C.
中科院分区：
文献类型：
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作者：
Schaap, Frank G.;Kremer, Andreas E.;Gaemers, Ingrid C.
在非酒精性脂肪性肝病 (NAFLD) 中，肝脏表达增加是成纤维细胞生长因子 21 (FGF21) 血清水平升高的原因，但潜在的分子机制尚不清楚。在本研究中，我们测试了代谢激素 FGF21 受内质网 (ER) 应激调节的假设，这种情况在包括 NAFLD 在内的许多疾病中都观察到，并导致称为未折叠蛋白反应 (UPR) 的适应性反应的激活。发现 ER 应激刺激可诱导 H4IIE 肝癌细胞和离体大鼠肝细胞中 Fgf21 mRNA 的表达。此外，腹腔注射内质网应激源衣霉素可诱导小鼠肝脏 FGF21 表达，并导致血清 FGF21 水平显着升高。 ER 应激对 FGF21 表达的影响可以通过 ATF4 的过度表达来模拟，ATF4 是 UPR PERK 分支的转录效应子。计算机分析显示 FGF21 启动子区域存在两个 ATF4 结合位点。这些元件的联合破坏，消除了 ER 应激或 ATF4 过表达诱导的 FGF21 启动子活性。这些发现表明 PERK/eIF2alpha/ATF4 级联参与 FGF21 的 ER 应激调节。这一概念的结果是，汇聚于 eIF2α 的其他细胞内应激信号传导途径可以调节 FGF21 的表达。事实上，营养（氨基酸剥夺）和氧化应激（亚砷酸盐）都被发现可诱导肝癌细胞和分离的大鼠肝细胞中 Fgf21 的表达。总之，FGF21 表达受到 ER 应激和其他细胞内应激信号通路的调节。我们的研究结果表明，脂肪肝中细胞应激的增加可能是 NAFLD 患者 FGF21 水平升高的原因。 (C) 2012 Elsevier Masson SAS。版权所有。
Increased hepatic expression is held responsible for elevated serum levels of fibroblast growth factor 21 (FGF21) in non-alcoholic fatty liver disease (NAFLD) but the underlying molecular mechanism is unclear. In the present study we tested the postulate that the metabolic hormone FGF21 is regulated by endoplasmic reticulum (ER) stress, a condition that is observed in a number of diseases including NAFLD and results in activation of an adaptive response known as the unfolded protein response (UPR). ER stress stimuli were found to induce expression of Fgf21 mRNA in H4IIE hepatoma cells and in isolated rat hepatocytes. Moreover, intraperitoneal injection of the ER stressor tunicamycin induced hepatic Fgf21 expression in mice and resulted in marked elevation of serum FGF21 levels. The effect of ER stress on FGF21 expression could be mimicked by overexpression of ATF4, a transcriptional effector of the PERK-branch of the UPR. In silico analysis revealed the presence of two binding sites for ATF4 in the FGF21 promoter region. Combined disruption of these elements, abrogated FGF21 promoter activity induced by ER stress or ATF4 overexpression. These findings implicate the PERK/eIF2alpha/ATF4 cascade in ER stress regulation of FGF21. A consequence of this notion is that other intracellular stress signaling pathways that converge at eIF2alpha, can regulate FGF21 expression. Indeed, both nutrient (amino acid deprivation) and oxidative stress (arsenite) were found to induce Fgf21 expression in hepatoma cells and isolated rat hepatocytes. In conclusion, FGF21 expression is regulated by ER stress and additional intracellular stress signaling pathways. Our findings suggest that increased cellular stress in fatty livers may underlie the elevated FGF21 levels observed in patients with NAFLD. (C) 2012 Elsevier Masson SAS. All rights reserved.