UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators.
UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators.
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DOI：
10.1016/j.devcel.2008.10.015
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发表时间：
2008-12
影响因子：
11.8
通讯作者：
Kaufman, Randal J.
中科院分区：
文献类型：
--
作者：
Rutkowski, D. Thomas;Wu, Jun;Back, Sung-Hoon;Callaghan, Michael U.;Ferris, Sean P.;Iqbal, Jahangir;Clark, Robert;Miao, Hongzhi;Hassler, Justin R.;Fornek, Jamie;Katze, Michael G.;Hussain, M. Mahmood;Song, Benbo;Swathirajan, Jayanth;Wang, Junying;Yau, Grace D. -Y.;Kaufman, Randal J.
未折叠蛋白反应（UPR）与代谢功能障碍有关，但尚不清楚ER破坏如何影响代谢途径。使用多层遗传学方法，我们发现ER应激传感通路（ATF6α，eIF2α，IRE1α）或ER质量控制（p58 IPK）基因消融的小鼠对ER应激有共同的失调反应，包括微泡性脂肪变性的发展。应激期间UPR途径的联合作用对ER蛋白加工能力的拯救可以防止调节脂质稳态的代谢转录因子子集的抑制。这种抑制部分是通过未解决的ER应激使转录抑制因子CHOP的表达永久化而发生的。因此，代谢基因表达网络直接响应ER稳态。这些结果揭示了ER稳态和代谢的转录调控之间的意外直接联系，并提出了ER应激可能导致微泡性脂肪变性的机制。
The unfolded protein response (UPR) is linked to metabolic dysfunction, yet it is not known how ER disruption might influence metabolic pathways. Using a multilayered genetic approach, we find that mice with genetic ablations of either ER stress sensing pathways (ATF6α, eIF2α, IRE1α), or of ER quality control (p58IPK), share a common dysregulated response to ER stress that includes the development of microvesicular steatosis. The rescue of ER protein processing capacity by the combined action of UPR pathways during stress prevents the suppression of a subset of metabolic transcription factors that regulate lipid homeostasis. This suppression occurs in part by unresolved ER stress perpetuating expression of the transcriptional repressor CHOP. As a consequence, metabolic gene expression networks are directly responsive to ER homeostasis. These results reveal an unanticipated direct link between ER homeostasis and the transcriptional regulation of metabolism and suggest mechanisms by which ER stress might underlie microvesicular steatosis.
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