UPR Pathways Combine to Prevent Hepatic Steatosis Caused by ER Stress-Mediated Suppression of Transcriptional Master Regulators

被引:502
作者
Rutkowski, D. Thomas [7 ]
Wu, Jun [7 ]
Back, Sung-Hoon [1 ]
Callaghan, Michael U. [2 ,7 ]
Ferris, Sean P. [7 ]
Iqbal, Jahangir [3 ]
Clark, Robert [1 ]
Miao, Hongzhi [4 ]
Hassler, Justin R. [7 ]
Fornek, Jamie [5 ]
Katze, Michael G. [5 ]
Hussain, M. Mahmood [3 ]
Song, Benbo [1 ]
Swathirajan, Jayanth [7 ]
Wang, Junying [7 ]
Yau, Grace D. -Y. [7 ]
Kaufman, Randal J. [1 ,6 ,7 ]
机构
[1] Univ Michigan, Med Ctr, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA
[2] Wayne State Univ, Dept Pediat, Detroit, MI 48201 USA
[3] Suny Downstate Med Ctr, Dept Anat & Cell Biol, Brooklyn, NY 11203 USA
[4] Univ Michigan, Med Ctr, Dept Pediat, Ann Arbor, MI 48109 USA
[5] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA
[6] Univ Michigan, Med Ctr, Dept Internal Med, Ann Arbor, MI 48109 USA
[7] Univ Michigan, Med Ctr, Dept Biol Chem, Ann Arbor, MI 48109 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1016/j.devcel.2008.10.015
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The unfolded protein response (UPR) is linked to metabolic dysfunction, yet it is not known how endoplasmic reticulum (ER) disruption might influence metabolic pathways. Using a multilayered genetic approach, we find that mice with genetic ablations of either ER stress-sensing pathways (ATF6 alpha, eIF2 alpha, IRE1 alpha) or of ER quality control (p58(IPK)) share a common dysregulated response to ER stress that includes the development of hepatic microvesicular steatosis. 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 fatty liver disease.
引用
收藏
页码:829 / 840
页数:12
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