Fibroblast Growth Factor 21 Is Regulated by the IRE1α-XBP1 Branch of the Unfolded Protein Response and Counteracts Endoplasmic Reticulum Stress-induced Hepatic Steatosis
Fibroblast Growth Factor 21 Is Regulated by the IRE1α-XBP1 Branch of the Unfolded Protein Response and Counteracts Endoplasmic Reticulum Stress-induced Hepatic Steatosis
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成纤维细胞生长因子 21 受未折叠蛋白反应的 IRE1 α-XBP1 分支调节并抵消内质网应激诱导的肝脂肪变性
DOI：
10.1074/jbc.m114.565960
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发表时间：
2014-10-24
影响因子：
4.8
通讯作者：
Jia, Wei-ping
中科院分区：
文献类型：
--
作者：
Jiang, Shan;Yan, Cheng;Jia, Wei-ping
背景：虽然两者都参与代谢稳态，但ER应激和FGF 21之间的相互关系仍不完全清楚。结果：FGF 21通过IRE 1-XBP 1通路直接上调，可减轻ER应激诱导的肝脂肪变性。结论：FGF 21作为UPR程序的代谢效应子，对脂代谢发挥反馈作用。重要性：这些发现揭示了一种将FGF 21的作用与代谢性内质网应激联系起来的调节机制。内质网（ER）应激激活了适应性未折叠蛋白反应（UPR），并代表了代谢功能障碍的关键机制。成纤维细胞生长因子21（FGF 21）是一种主要由肝脏分泌的激素，对碳水化合物和脂质的代谢产生广泛的影响。尽管在肥胖和非酒精性脂肪肝的动物模型和人类受试者中已经记录了FGF 21循环水平的增加，但代谢性ER应激和FGF 21之间的功能性相互联系尚不完全清楚。在这里，我们报告说，增加内质网应激沿着FGF 21表达的同时升高与饮食诱导的肥胖小鼠和人类患者非酒精性脂肪肝的发生有关。腹腔注射ER应激子衣霉素导致小鼠肝脏脂肪变性，伴随着三个典型的UPR分支的激活，并增加了FGF 21的表达。此外，UPR的IRE 1-XBP 1通路可直接激活Fgf 21的转录表达。在小鼠中施用重组FGF 21减轻衣霉素诱导的肝脏脂肪变性，同时减少eIF 2-ATF 4-CHOP信号传导。综上所述，这些结果表明，FGF 21是细胞UPR程序的一个不可或缺的生理组成部分，其通过抵消ER应激对脂质代谢产生有益的反馈作用。
Background: Although both are involved in metabolic homeostasis, the interconnection between ER stress and FGF21 remains incompletely understood. Results: Directly up-regulated by the IRE1-XBP1 pathway, FGF21 could alleviate ER stress-induced liver steatosis. Conclusion: FGF21 acts as a metabolic effector of the UPR program, exerting feedback effects upon lipid metabolism. Significance: These findings reveal a regulatory mechanism linking FGF21 actions to metabolic ER stress.Endoplasmic reticulum (ER) stress activates the adaptive unfolded protein response (UPR) and represents a critical mechanism that underlies metabolic dysfunctions. Fibroblast growth factor 21 (FGF21), a hormone that is predominantly secreted by the liver, exerts a broad range of effects upon the metabolism of carbohydrates and lipids. Although increased circulating levels of FGF21 have been documented in animal models and human subjects with obesity and nonalcoholic fatty liver disease, the functional interconnections between metabolic ER stress and FGF21 are incompletely understood. Here, we report that increased ER stress along with the simultaneous elevation of FGF21 expression were associated with the occurrence of nonalcoholic fatty liver disease both in diet-induced obese mice and human patients. Intraperitoneal administration of the ER stressor tunicamycin in mice resulted in hepatic steatosis, accompanied by activation of the three canonical UPR branches and increased the expression of FGF21. Furthermore, the IRE1-XBP1 pathway of the UPR could directly activate the transcriptional expression of Fgf21. Administration of recombinant FGF21 in mice alleviated tunicamycin-induced liver steatosis, in parallel with reduced eIF2-ATF4-CHOP signaling. Taken together, these results suggest that FGF21 is an integral physiological component of the cellular UPR program, which exerts beneficial feedback effects upon lipid metabolism through counteracting ER stress.