Double-Stranded RNA-Dependent Protein Kinase Links Pathogen Sensing with Stress and Metabolic Homeostasis

Department of Genetics & Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Cell (Impact Factor: 32.24). 02/2010; 140(3):338-48. DOI: 10.1016/j.cell.2010.01.001
Source: PubMed

ABSTRACT As chronic inflammation is a hallmark of obesity, pathways that integrate nutrient- and pathogen sensing pathways are of great interest in understanding the mechanisms of insulin resistance, type 2 diabetes, and other chronic metabolic pathologies. Here, we provide evidence that double-stranded RNA-dependent protein kinase (PKR) can respond to nutrient signals as well as endoplasmic reticulum (ER) stress and coordinate the activity of other critical inflammatory kinases such as the c-Jun N-terminal kinase (JNK) to regulate insulin action and metabolism. PKR also directly targets and modifies insulin receptor substrate and hence integrates nutrients and insulin action with a defined pathogen response system. Dietary and genetic obesity features marked activation of PKR in adipose and liver tissues and absence of PKR alleviates metabolic deterioration due to nutrient or energy excess in mice. These findings demonstrate PKR as a critical component of an inflammatory complex that responds to nutrients and organelle dysfunction.

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Available from: Masato Furuhashi, Sep 25, 2015
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    • "Cells were then treated with 0.2 mM LA for 48 h, a concentration that can be achieved in human blood plasma after ingestion of a supplement [21]. LA was dissolved in ethanol to prepare a stock solution of 100 mM, and glucose was dissolved in water to prepare a solution of 1 M. Palmitic acid (PA) was prepared as previously described [22]. For cell transfection, 1.5 g of plasmid DNAs was transfected into McA cells as previously described [23] "
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    ABSTRACT: The activation of sterol regulatory element binding proteins (SREBPs) is regulated by insulin-induced genes 1 and 2 (Insig-1 and Insig-2) and SCAP. We previously reported that feeding R-α-lipoic acid (LA) to Zucker diabetic fatty (ZDF) rats improves severe hypertriglyceridemia. In this study, we investigated the role of cyclic AMP-responsive element binding protein H (CREBH) in the lipid-lowering mechanism of LA and its involvement in the SREBP-1c and Insig pathway. Incubation of McA cells with LA (0.2 mM) or glucose (6 mM) stimulated activation of CREBH. LA treatment further induced mRNA expression of Insig-1 and Insig-2a, but not Insig-2b, in glucose-treated cells. In vivo, feeding LA to obesity-induced hyperlipidemic ZDF rats activated hepatic CREBH and stimulated transcription and translation of Insig-1 and Insig-2a. Activation of CREBH and Insigs induced by LA suppressed processing of SREBP-1c precursor into nuclear SREBP-1c, which subsequently inhibited expression of genes involved in fatty acid synthesis, including FASN, ACC and SCD-1, and reduced triglyceride (TG) contents in both glucose-treated cells and ZDF rat livers. Additionally, LA treatment also decreased abundances of very low density lipoprotein (VLDL)-associated apolipoproteins, apoB100 and apoE, in glucose-treated cells and livers of ZDF rats, leading to decreased secretion of VLDL and improvement of hypertriglyceridemia. This study unveils a novel molecular mechanism whereby LA lowers TG via activation of hepatic CREBH and increased expression of Insig-1 and Insig-2a to inhibit de novo lipogenesis and VLDL secretion. These findings provide novel insight into the therapeutic potential of LA as an anti-hypertriglyceridemia dietary molecule. Copyright © 2015 Elsevier Inc. All rights reserved.
    The Journal of nutritional biochemistry 05/2015; 26(9). DOI:10.1016/j.jnutbio.2015.03.011 · 3.79 Impact Factor
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    • "JNK activity was found induced in many tissues of obese and insulinresistant mice (Hirosumi et al. 2002) (Fig. 2). Mechanistically, JNK activation can occur through the induction of endoplasmic reticulum stress (Hotamisligil 2010), depending on the activity of double-stranded RNA-dependent protein kinase (PKR) (Nakamura et al. 2010). Alternatively, saturated fatty acids through binding of toll-like receptors (Shi et al. 2006; Tsukumo et al. 2007) or through activation of the protein kinase C-mediated activation of the mixed-lineage protein kinase (MLK) group of MAP kinase kinase kinases (MAPKKKs) (Kant et al. 2013) may also activate JNK. "
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    ABSTRACT: Low-grade inflammation is an established pathological condition that contributes to the development of obesity, insulin resistance and type 2 diabetes. Metabolic inflammation is dependent on multiple signalling events. In an overnutrition state, canonical inflammatory pathways are induced by inflammatory cytokines and lipid species. They can also be triggered through inflammasome activation as well as through cellular stress provoked by the unfolded protein response at the endoplasmic reticulum as well as by reactive oxygen species. In this chapter, we summarize the current knowledge about signalling events within the cell and describe how they impact on metabolic inflammation and whole-body metabolism. We particularly highlight the interplay between different signalling pathways that link low-grade inflammation responses to the inactivation of the insulin receptor pathway, ultimately leading to insulin resistance, a hallmark of type 2 diabetes.
    Handbook of experimental pharmacology 04/2015; DOI:10.1007/164_2015_4
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    • "Notably, PKR activity is highly correlated with JNK activation, and in turn, JNK may phosphorylate TRBP, indicating a regulatory loop between these kinases via TRBP, which may be key to their activation in metabolic context. As the assembly of PKR with RLC is highly associated with PKR and JNK activation, and because PKR can also participate in inflammatory activity (Carvalho-Filho et al., 2012; Lu et al., 2012; Nakamura et al., 2010), TRBP phosphorylation may be a core component of a signaling node representing the metabolic inflammasome (metaflammasome ). Finally, our findings indicate that the inhibition of PKR and TRBP function may result in simultaneous relief from multiple stress responses and may provide new opportunities for clinical applications against chronic stress-related diseases, including obesity-induced metabolic disease and cancer. "
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    ABSTRACT: 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 (eIF2α) 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 eIF2α 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. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 04/2015; 274(2). DOI:10.1016/j.celrep.2015.03.021 · 8.36 Impact Factor
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