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: 10.37). 01/2009; 15(6):829-40. DOI: 10.1016/j.devcel.2008.10.015
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Justin R Hassler, Sep 03, 2015
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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 · 2.85 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "Together, these data indicate that hepatic SIRT7 autonomously prevents the development of fatty liver. SIRT7 Activation Is a Critical Event of the UPR to Alleviate ER Stress Activation of the UPR pathways induces inflammation (Hotamisligil , 2010), perturbs hepatic lipid metabolism by modulating lipogenesis and lipoprotein metabolism (Kammoun et al., 2009; Lee et al., 2008; Ota et al., 2008; Rutkowski et al., 2008; So et al., 2012; Wang et al., 2012; Zhang et al., 2011), and results in the development of fatty liver, reminiscent of essential aspects of SIRT7 KO phenotype in the liver (Figure 1). We therefore hypothesized that SIRT7 might be an essential regulator of the UPR. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Nonalcoholic fatty liver disease is the most common chronic liver disorder in developed countries. Its pathogenesis is poorly understood, and therapeutic options are limited. Here, we show that SIRT7, an NAD(+)-dependent H3K18Ac deacetylase, functions at chromatin to suppress ER stress and prevent the development of fatty liver disease. SIRT7 is induced upon ER stress and is stabilized at the promoters of ribosomal proteins through its interaction with the transcription factor Myc to silence gene expression and to relieve ER stress. SIRT7-deficient mice develop chronic hepatosteatosis resembling human fatty liver disease. Myc inactivation or pharmacological suppression of ER stress alleviates fatty liver caused by SIRT7 deficiency. Importantly, SIRT7 suppresses ER stress and reverts the fatty liver disease in diet-induced obese mice. Our study identifies SIRT7 as a cofactor of Myc for transcriptional repression and delineates a druggable regulatory branch of the ER stress response that prevents and reverts fatty liver disease.
    Cell Reports 11/2013; 5(3). DOI:10.1016/j.celrep.2013.10.007 · 8.36 Impact Factor
Show more