期刊
CELL REPORTS
卷 11, 期 2, 页码 295-307出版社
CELL PRESS
DOI: 10.1016/j.celrep.2015.03.021
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资金
- National Institutes of Health [DK052539, HL125753]
- International Human Frontier Science Program
- NIDDK of the Digestive Disease Research Core Center in Cincinnati [P30 DK078392]
- American Heart Association
- PRESTO from the Japan Science and Technology Agency
Aberrant stress and inflammatory responses are key factors in the pathogenesis of obesity and metabolic dysfunction, and the double-stranded RNA-dependent kinase (PKR) has been proposed to play an important role in integrating these pathways. Here, we report the formation of a complex between PKR and TAR RNA-binding protein (TRBP) during metabolic and obesity-induced stress, which is critical for the regulation of eukaryotic translation initiation factor 2 alpha (eIF2 alpha) phosphorylation and c-Jun N-terminal kinase (JNK) activation. We show that TRBP phosphorylation is induced in the setting of metabolic stress, leading to PKR activation. Suppression of hepatic TRBP reduced inflammation, JNK activity, and eIF2 alpha phosphorylation and improved systemic insulin resistance and glucose metabolism, while TRBP overexpression exacerbated the impairment in glucose homeostasis in obese mice. These data indicate that the association between PKR and TRBP integrates metabolism with translational control and inflammatory signaling and plays important roles in metabolic homeostasis and disease.
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