Targeting endoplasmic reticulum stress in metabolic disease

Sanford-Burnham Medical Research Institute, Del E. Webb Neuroscience, Aging and Stem Cell Research Center , La Jolla, CA 92037 , USA.
Expert Opinion on Therapeutic Targets (Impact Factor: 5.14). 01/2013; 17(4). DOI: 10.1517/14728222.2013.756471
Source: PubMed


Endoplasmic reticulum (ER) stress, a condition that dramatically affects protein folding homeostasis in cells, has been associated with a number of metabolic diseases. Emerging preclinical and clinical evidence supports the notion that pharmacological modulators of ER stress have therapeutic potential as novel treatments of metabolic disorders.

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In this review, the molecular mechanisms of ER stress and the unfolded protein response (UPR) in the pathogenesis of metabolic diseases are discussed, highlighting the roles of various UPR components revealed using disease models in mice. Special emphasis is placed on the use of novel small molecules in animal disease models and human pathologies, including type 2 diabetes, obesity, fatty liver disease, and atherosclerosis.

Expert opinion:
ER stress is a highly promising therapeutic target for metabolic disease. Small molecular chemical chaperones have already demonstrated therapeutic efficacy in animal and human studies. The emergence of compounds that target specific UPR signaling pathways will provide more options for this purpose. Although the findings are promising, more studies are needed to elucidate the efficacy and side effects of these small molecules for future use in humans.

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Available from: Stewart Siyan Cao
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    • "In mammals, the liver is the master organ in regulating glucose metabolism. Insulin resistance in the liver promotes gluconeogenesis and lipogenesis, which contributes to subsequent hyperglycemia and hyperlipidemia (Cao and Kaufman, 2013b). In the setting of ER stress, insulin resistance develops through IRE1a-mediated activation of JNK and IKK, which subsequently inhibits insulin action by downstream serine phosphorylation of insulin receptor substrate (IRS) 1 and 2. In addition to IRE1a-mediated activation, JNK can be induced by CAMKII and eIF2a kinase PKR in the setting of ER stress to induce insulin resistance (Timmins et al., 2009). "
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    ABSTRACT: The endoplasmic reticulum (ER) is a critical organelle for normal cell function and homeostasis. Disturbance in the protein folding process in the ER, termed ER stress, leads to the activation of unfolded protein response (UPR) that encompasses a complex network of intracellular signaling pathways. The UPR can either restore ER homeostasis or activate pro-apoptotic pathways depending on the type of insults, intensity and duration of the stress, and cell types. ER stress and the UPR have recently been linked to inflammation in a variety of human pathologies including autoimmune, infectious, neurodegenerative, and metabolic disorders. In the cell, ER stress and inflammatory signaling share extensive regulators and effectors in a broad spectrum of biological processes. In spite of different etiologies, the two signaling pathways have been shown to form a vicious cycle in exacerbating cellular dysfunction and causing apoptosis in many cells and tissues. However, the interaction between ER stress and inflammation in many of these diseases remains poorly understood. Further understanding of the biochemistry, cell biology, and physiology may enable the development of novel therapies that spontaneously target these pathogenic pathways. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jul 2015 · Journal of Cellular Physiology
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    • "Even more, whereas the activation of the UPR following infection with WNV has been well documented (Medigeshi et al., 2007; Ambrose and Mackenzie, 2011, 2013), the induction of an autophagic response in WNV-infected cells still remains contentious, with evidences supporting both the upregulation (Beatman et al., 2012; Kobayashi et al., 2014) or not (Vandergaast and Fredericksen, 2012) of this pathway. Both autophagy and UPR constitute druggable metabolic pathways under evaluation for multiple therapeutic interventions (Suh et al., 2012; Cao and Kaufman, 2013). "
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    ABSTRACT: West Nile virus (WNV) is a neurotropic mosquito-borne flavivirus responsible for outbreaks of meningitis and encephalitis. Whereas the activation of autophagy in cells infected with other flaviviruses is well known, the interaction of WNV with the autophagic pathway still remains unclear and there are reports describing opposite findings obtained even analyzing the same viral strain. To clarify this controversy, we first analyzed the induction of autophagic features in cells infected with a panel of WNV strains. WNV was determined to induce autophagy in a strain dependent manner. We observed that all WNV strains or isolates analyzed, except for the WNV NY99 used, upregulated the autophagic pathway in infected cells. Interestingly, a variant derived from this WNV NY99 isolated from a persistently infected mouse increased LC3 modification and aggregation. Genome sequencing of this variant revealed only two non-synonymous nucleotide substitutions when compared to parental NY99 strain. These nucleotide substitutions introduced one amino acid replacement in NS4A and other in NS4B. Using genetically engineered viruses we showed that introduction of only one of these replacements was sufficient to upregulate the autophagic pathway. Thus, in this work we have shown that naturally occurring point mutations in the viral non-structural proteins NS4A and NS4B confer WNV with the ability to induce the hallmarks of autophagy such as LC3 modification and aggregation. Even more, the differences on the induction of an autophagic response observed among WNV variants in infected cells did not correlate with alterations on the activation of the unfolded protein response (UPR), suggesting an uncoupling of UPR and autophagy during flavivirus infection. The findings here reported could help to improve the knowledge of the cellular processes involved on flavivirus-host cell interactions and contribute to the design of effective strategies to combat these pathogens.
    Full-text · Article · Jan 2015 · Frontiers in Microbiology
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    • "An important challenge will be the analysis of autophagy and UPR during flavivirus infection in vivo using animal models, of course, having in mind the complex biology of these pathogens that include infection of different host cells within their infectious cycle, which could complicate the interpretation of these studies. In fact, autophagy and UPR currently represent druggable pathways under evaluation for the treatment of multiple human disorders (Suh et al., 2012; Cao and Kaufman, 2013), and recent studies have revealed that pharmacological activation of autophagy can be protective in vivo against flavivirus infection (Shoji-Kawata et al., 2013). "
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    ABSTRACT: The Flavivirus is a genus of RNA viruses that includes multiple long known human, animal, and zoonotic pathogens such as Dengue virus, yellow fever virus, West Nile virus, or Japanese encephalitis virus, as well as other less known viruses that represent potential threats for human and animal health such as Usutu or Zika viruses. Flavivirus replication is based on endoplasmic reticulum-derived structures. Membrane remodeling and accumulation of viral factors induce endoplasmic reticulum stress that results in activation of a cellular signaling response termed unfolded protein response (UPR), which can be modulated by the viruses for their own benefit. Concomitant with the activation of the UPR, an upregulation of the autophagic pathway in cells infected with different flaviviruses has also been described. This review addresses the current knowledge of the relationship between endoplasmic reticulum stress, UPR, and autophagy in flavivirus-infected cells and the growing evidences for an involvement of these cellular pathways in the replication and pathogenesis of these viruses.
    Full-text · Article · Jun 2014 · Frontiers in Microbiology
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