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

Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
Developmental Cell (Impact Factor: 9.71). 01/2009; 15(6):829-40. DOI: 10.1016/j.devcel.2008.10.015
Source: PubMed


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 (ATF6alpha, eIF2alpha, IRE1alpha) 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.

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    • "We conclude that not all UPR subclasses cause FLD and that inducing an adaptive UPR could be exploited therapeutically to reduce FLD. RESULTS Tm is the most efficient steatosis-inducing stressor Tm causes UPR activation and steatosis in all species studied (Cinaroglu et al., 2011; Rutkowski et al., 2008; Teske et al., 2011; Thakur et al., 2011; Yamamoto et al., 2010; Zhang et al., 2011) but whether other stressors also cause FLD is not known. We treated zebrafish larvae with Tm and two other commonly used secretory pathway stressors, Tg and Brefeldin A (BFA), and assessed steatosis and UPR induction in the liver. "
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    ABSTRACT: The unfolded protein response (UPR) is a complex network of sensors and target genes that ensure efficient folding of secretory proteins in the endoplasmic reticulum (ER). UPR activation is mediated by three main sensors, which regulate the expression of hundreds of targets. UPR activation can result in outcomes ranging from enhanced cellular function to cell dysfunction and cell death. How this pathway causes such different outcomes is unknown. Fatty liver disease (steatosis) is associated with markers of UPR activation and robust UPR induction can cause steatosis; however, in other cases, UPR activation can protect against this disease. By assessing the magnitude of activation of UPR sensors and target genes in the liver of zebrafish larvae exposed to three commonly used ER stressors (tunicamycin, thapsigargin and Brefeldin A), we have identified distinct combinations of UPR sensors and targets (i.e. subclasses) activated by each stressor. We found that only the UPR subclass characterized by maximal induction of UPR target genes, which we term a stressed-UPR, induced steatosis. Principal component analysis demonstrated a significant positive association between UPR target gene induction and steatosis. The same principal component analysis showed significant correlation with steatosis in samples from patients with fatty liver disease. We demonstrate that an adaptive UPR induced by a short exposure to thapsigargin prior to challenging with tunicamycin reduced both the induction of a stressed UPR and steatosis incidence. We conclude that a stressed UPR causes steatosis and an adaptive UPR prevents it, demonstrating that this pathway plays dichotomous roles in fatty liver disease.
    Disease Models and Mechanisms 07/2014; 7(7):823-35. DOI:10.1242/dmm.014472 · 4.97 Impact Factor
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    • "NAFLD is an emerging and now the most common cause of chronic liver enzyme elevations and cryptogenic cirrhosis because of the prevalence of obesity [70]. The failure of the UPR to rapidly re-establish ER homoeostasis via genetic ablation of eIF2α, IRE1α or ATF6α results in hepatic steatosis, where the capacity to oxidize fatty acids is impaired [71]. This is further exacerbated by dysfunction in the lipoprotein secretion pathway. "
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    ABSTRACT: Stress pathways monitor intracellular systems and deploy a range of regulatory mechanisms in response to stress. One of the best-characterized pathways, the unfolded protein response (UPR), is an intracellular signal transduction pathway that monitors endoplasmic reticulum (ER) homeostasis. Its activation is required to alleviate the effects of ER stress and is highly conserved from yeast to human. Although metazoans have three UPR outputs, yeast cells rely exclusively on the inositol-requiring enzyme-1 (Ire1) pathway, which is conserved in all Eukaryotes. In general, the UPR program activates hundreds of genes to alleviate ER stress but it can lead to apoptosis if the system fails to restore homeostasis. In this review, we summarize the major advances in understanding the response to ER stress in S. cerevisiae, S. pombe, and humans. The contribution of solved protein structures to a better understanding of the UPR pathway is discussed. Finally, we cover the interplay of ER stress in the development of diseases.
    Bioscience Reports 06/2014; 34(4). DOI:10.1042/BSR20140058 · 2.64 Impact Factor
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    • "a 1.5-fold or more, p <0.05, in at least 2 of the arrays described in Marciniak et al. (2004); Wu et al. (2007); and Rutkowski et al. (2008). and gluconeogenesis and hyperglycemia could be suppressed in diabetic animals by ATF6 overexpression. "
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    ABSTRACT: The mammalian unfolded protein response (UPR) is propagated by three ER-resident transmembrane proteins, each of which initiates a signaling cascade that ultimately culminates in production of a transcriptional activator. The UPR was originally characterized as a pathway for upregulating ER chaperones, and a comprehensive body of subsequent work has shown that protein synthesis, folding, oxidation, trafficking, and degradation are all transcriptionally enhanced by the UPR. However, the global reach of the UPR extends to genes involved in diverse physiological processes having seemingly little to do with ER protein folding, and this includes a substantial number of mRNAs that are suppressed by stress rather than stimulated. Through multiple non-canonical mechanisms emanating from each of the UPR pathways, the cell dynamically regulates transcription and mRNA degradation. Here we highlight these mechanisms and their increasingly appreciated impact on physiological processes.
    Frontiers in Genetics 12/2013; 4:256. DOI:10.3389/fgene.2013.00256
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