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The Unfolded Protein Response, Inflammation, Oscillators, and Disease: a Systems Biology Approach

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The Unfolded Protein Response, Inflammation, Oscillators, and Disease: a Systems Biology Approach Endoplasm. Reticul. Stress Dis. 2015; 2, 30–52 Review article Open Access Rafael Rangel-Aldao The unfolded protein response, inflammation, oscillators, and disease: a systems biology approach Abstract: Non-communicable diseases (NCDs) such as mortality by NCDs, namely, cardio- and cerebrovascular cardiovascular disease, cancers, diabetes and obesity are disease, cancers, and diabetes [1]. Such diseases are responsible for about two thirds of mortality worldwide, preventable by a host of lifestyle measures that include and all of these ailments share a common low-intensity large-scale control of tobacco and alcohol consumption, systemic chronic inflammation, endoplasmic reticulum comprehensive changes in dietary intake of sugars, salt, stress (ER stress), and the ensuing Unfolded Protein harmful fats, and increasing daily consumption of fresh Response (UPR). These adaptive mechanisms are also fruits and vegetables. These, and additional preventive responsible for significant metabolic changes that feedback measures such as early clinical interventions, may help to with the central clock of the suprachiasmatic nucleus significantly reduce the risk to NCDs [2]. (SCN) of the hypothalamus, as well as with oscillators Prevention of NCDs, in particular the three major of peripheral tissues. In this review we attempt to use a diseases referred above, and additionally obesity, is of systems biology approach to explore such interactions as paramount importance given the close pathophysiological a whole; to answer two fundamental questions: (1) how relationship between them [3]. What seems to link them all dependent are these adaptive responses and subsequent are interlocked complex networks [4,5], controlling signal events leading to NCD with their state of synchrony with transduction of adaptive responses such as the unfolded the SCN and peripheral oscillators? And, (2) How could protein response, UPR [6,7], systemic chronic inflammation modifiers of the activity of SCN for instance, food intake, [8], and the central clock of the suprachiasmatic nucleus exercise, and drugs, be potentially used to modulate (SCN) of the hypothalamus [9-11]. systemic inflammation and ER stress to ameliorate or even Through systems biology it is now possible to get prevent NCDs? a preliminary understanding on how such interplay of biological information is organized into complex networks Keywords: Systems biology, inflammation, circadian, transducing signals from a host of environmental stimuli oscillators, metabolism, communicable diseases, UPR, into adaptive responses that could potentially end in stress systemic chronic inflammation and disease [12, 13]. Using the system biology approach, the networks can be understood as organizing into stacks in hierarchical DOI 10.1515/ersc-2015-0003 order; of numerous functional modules controlled by few Received: October 21, 2014; Revised: December 22, 2014; Accepted: nodes (hubs), made of key regulator molecules connecting January 2, 2015 every module through a myriad of positive and negative feedback loops [14, 15]. 1 Introduction These networks can be probed to study in detail how the signal transduction machinery connects, for instance, Non-communicable diseases (NCDs) are responsible energy metabolism and the systemic chronic inflammation for about two thirds (65.5%) of worldwide mortality. By preceding most if not all NCDs [12, 13, 16]. In this respect, 2010, just three ailments accounted for 64.35% of all in the last few years many groups of researchers have uncovered ample evidence pointing to energy metabolism *Corresponding authors: Rafael Rangel-Aldao: Department of as a key link to the UPR and inflammation, with metabolic Technology of Biological Processes and Group of Digital Science, risk factors that may eventually lead to some of the clinical Simon Bolivar University, Caracas, 1083, Venezuela, manifestations of the big four NCDs [7, 17, 18]. Email: [email protected] © 2015 Rafael Rangel-Aldao, licensee De Gruyter Open. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License. Unfolded protein response and oscillators 31 Metabolic risk factors for NCDSs include high blood response, both at the epidemiological, clinical and levels of triglycerides (TG), low levels of high-density experimental levels. Although inflammation is a lipoproteins (HDL), high blood pressure, impaired fasting physiological response to limit bodily harm to many types glycaemia, abusive alcohol ingestion, tobacco, physical of aggressions, when deregulated or chronic, may become inactivity and excess food intake. Additional risk factors collateral damage and immune pathological to the host include elevated circulating inflammatory markers (i.e. [26]. Thus systemic chronic inflammation appears to C-reactive protein, tumor necrosis factor, interleukin-6), be linked to homeostatic disequilibria (i.e. tissue stress) and reduced levels of anti-inflammatory hormones such of one or more networks of adaptive response, which as adiponectin [19-22]. are not necessarily related to the classical aggressors of Another major development with practical host defense or tissue repair (i.e. infections and tissue applications from the information systems underlying damage). This is the case in cardiovascular disease, CVD such physiological and biochemical phenomena, is the [12], cancers [3], type 2 diabetes and obesity [8]. realization that energy metabolism is tightly regulated by Perhaps the earliest convincing evidence of this a web of biological oscillators distributed in peripheral homeostatic disequilibrium was the demonstration tissues, and entrained by environmental changes that in 1993, of the overexpression of tumor necrosis follow a circadian rhythm dictated by the SCN [10, 23-25] factor-α (TNF-α) in adipose cells of obese and diabetic In this review we will attempt to use a systems experimental animals [27]. Tumor necrosis factor-α is biology approach to explore such interactions as a whole capable of altering glucose homeostasis by targeting and to get at least some partial answers to two fundamental inhibiting GLUT4 translocation to the plasma membrane questions regarding the role of ER stress on disease: by tissue-specific mechanisms [28]. Furthermore, [1] how dependent is the UPR and subsequent events adipocytes from obese animals communicate their stress referred above, to its state of synchrony with the SCN and condition to neighboring macrophages by secreting peripheral oscillators? And, [2] How could modifiers of the monocyte chemoattractant protein–1 (MCP-1), resulting activity of SCN, (for example, by means of changing food in macrophage infiltration into adipose tissue and intake, exercise, and drugs) be used to modulate ER stress augmented hepatic fat accumulation. These effects can and systemic inflammation to ameliorate or even prevent be significantly reduced in MCP-1 homozygous KO mice NCDs? when compared with WT animals [29]. These results In answering the above questions, we will first are, therefore, consistent with the role of tissue-resident delve into the relationships between chronic inflammation, macrophages as monitors of cell stress to maintain the ER and the UPR, and NCDs. Each of these topics will homeostasis [30]. be discussed, with specific examples relating to common These cell-cell interactions of adipocytes with tissue- NCDs, including heart disease, diabetes, and cancers. Our resident macrophages, via adipokines or adipocytokines analysis will begin broadly; the first part of the review will and cytokines, can become maladaptive and produce be devoted to the inflammatory response and NCDs. The collateral damage in the form of insulin resistance in review will then narrow into an in-depth discussion of the adipose tissue. Such communications can also cause a progenitors of chronic inflammation, namely ER stress wide range of systemic effects of inflammation leading to and the subsequent UPR pathway. Following that, we a vicious circle of more obesity and type 2 diabetes [26]. will again broaden the discussion to show the crosstalk Adipokines other than MCP-1 and TNF-α, cover a wide between the UPR, the SCN, and peripheral oscillators. range of chemical mediators, amid them interleukin-6 Finally, we will link chronic inflammation, ER stress and (IL-6), leptin, resistin, adiponectin, plasminogen activator the UPR, and oscillators, concluding with a discussion inhibitor (PAI-1), visfatin, apelin, omentin, and nefastin, on the potential implications for treatment of NCDs as among others [12]. The production of such bioactive discovered through the systems biology framework. mediators would explain the close association of systemic chronic inflammation with obesity, and also with cardiovascular disease [31]. 2 The link of NCDs to Systemic The role of systemic chronic inflammation on Chronic Inflammation CVD, with macrophages as protagonists, has been well documented for common ailments such as atherosclerosis, A considerable body of evidence accumulated in the last myocardial infarction and heart failure [32]. In short, the twenty years shows a causal relationship between the involvement of inflammation in CVD starts very early on onset of major NCDs with networks of the inflammatory with the retention of Apo lipoprotein (Apo) B-containing 32 R.Rangel-Aldao lipoproteins by the intima of arteries in regions of damage. The net effect of either pathway is the recruitment disturbed blood flow. Such lipid accumulation prompts and infiltration of neoplastic tissue by inflammatory
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