CHOP deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes

Howard Hughes Medical Institute and Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Journal of Clinical Investigation (Impact Factor: 13.77). 10/2008; 118(10):3378-89. DOI: 10.1172/JCI34587
Source: PubMed

ABSTRACT The progression from insulin resistance to type 2 diabetes is caused by the failure of pancreatic beta cells to produce sufficient levels of insulin to meet the metabolic demand. Recent studies indicate that nutrient fluctuations and insulin resistance increase proinsulin synthesis in beta cells beyond the capacity for folding of nascent polypeptides within the endoplasmic reticulum (ER) lumen, thereby disrupting ER homeostasis and triggering the unfolded protein response (UPR). Chronic ER stress promotes apoptosis, at least in part through the UPR-induced transcription factor C/EBP homologous protein (CHOP). We assessed the effect of Chop deletion in multiple mouse models of type 2 diabetes and found that Chop-/- mice had improved glycemic control and expanded beta cell mass in all conditions analyzed. In both genetic and diet-induced models of insulin resistance, CHOP deficiency improved beta cell ultrastructure and promoted cell survival. In addition, we found that isolated islets from Chop-/- mice displayed increased expression of UPR and oxidative stress response genes and reduced levels of oxidative damage. These findings suggest that CHOP is a fundamental factor that links protein misfolding in the ER to oxidative stress and apoptosis in beta cells under conditions of increased insulin demand.

  • Source
    • "showed that CHOP mediated the activation of Ero1a expression during ER stress ( Song et al . , 2008 ) and thus aggravated the accu - mulation of ROS in ER within stressed cells , consistent with our present finding ( Fig . 3B ) . Furthermore , CHOP can induce apoptosis via a direct inhibition of Bcl - 2 transcription and induction of Bim expression ( Dou et al . , 2012 ; McCullough et al . , 2001 ; Puthalakath et al . , 2007 ) . Previ"
    [Show abstract] [Hide abstract]
    ABSTRACT: Excess accumulation of endogenous all-trans-retinal (atRAL) contributes to degeneration of the retinal pigment epithelium (RPE) and photoreceptor cells, and plays a role in the etiologies of age-related macular degeneration (AMD) and Stargardt's disease. In this study, we reveal that human RPE cells tolerate exposure of up to 5 μM atRAL without deleterious effects, but higher concentrations are detrimental and induce cell apoptosis. atRAL treatment significantly increased production of intracellular reactive oxygen species (ROS) and up-regulated mRNA expression of Nrf2, HO-1, and γ-GCSh within RPE cells, thereby causing oxidative stress. ROS localized to mitochondria and endoplasmic reticulum (ER). ER resident molecular chaperone BiP, a marker of ER stress, was up-regulated at the translational level, and meanwhile, the PERK-eIF2α-ATF4 signaling pathway was activated. Expression levels of ATF4, CHOP, and GADD34 in RPE cells increased in a concentration-dependent manner after incubation with atRAL. Salubrinal, a selective inhibitor of ER stress, alleviated atRAL-induced cell death. The antioxidant N-acetylcysteine (NAC) effectively blocked RPE cell loss and ER stress activation, suggesting that atRAL-induced ROS generation is responsible for RPE degeneration and is an early trigger of ER stress. Furthermore, the mitochondrial transmembrane potential was lost after atRAL exposure, and was followed by caspase-3 activation and PARP cleavage. The results demonstrate that atRAL-driven ROS overproduction induced ER stress is involved in cellular mitochondrial dysfunction and apoptosis of RPE cells.
    Toxicological Sciences 10/2014; 143(1). DOI:10.1093/toxsci/kfu223 · 4.48 Impact Factor
  • Source
    • "During hypoxia, generation of ROS increases both in mitochondria (Brunelle et al., 2005) and the ER, partly through UPR-mediated induction of ERO1a (Marciniak et al., 2004; Song et al., 2008). Accordingly, a key function of the ISR is to defend against oxidative stress, primarily by increasing biosynthesis of the antioxidant glutathione (Harding et al., 2003). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The combination of relative nutrient deprivation and dysregulation of protein synthesis make malignant cells especially prone to protein misfolding. Endoplasmic reticulum stress, which results from protein misfolding within the secretory pathway, has a profound effect on cancer cell proliferation and survival. In this review, we examine the evidence implicating endoplasmic reticulum dysfunction in the pathology of cancer and discuss how recent findings may help to identify novel therapeutic targets.
    Cancer cell 05/2014; 25(5):563-573. DOI:10.1016/j.ccr.2014.03.015 · 23.89 Impact Factor
  • Source
    • "Knockout of Chop delays the onset of diabetes by about 8 weeks in the Akita mouse model due to protection of beta cells from apoptosis (Oyadomari et al., 2002). When Chop-deficient animals are crossed with obese db/db mice, beta cell death and diabetes are prevented (Song et al., 2008). Under obese and insulin-resistant conditions, beta cells are subjected to dramatically enhanced and sustained ER stress due to the increased demand for insulin. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic beta cells rely heavily on the endoplasmic reticulum (ER) to process folding and posttranslational modification of a large amount of insulin and many other proteins and are therefore vulnerable to ER stress. The role of the ER is thus crucial in the regulation of beta cell function and survival through the unfolded protein response (UPR) pathways. However, the UPR can either allow cells to survive by adapting to stress or kill cells through apoptosis in a context-dependent manner. How cell fate is determined following UPR activation remains enigmatic. In this review, we discuss the molecular mechanisms linking ER stress to beta cell survival or apoptosis. Specifically, we focus on the role of the cellular inhibitor of apoptosis protein-1 and propose a new model for understanding survival of beta cells undergoing ER stress.
    Vitamins & Hormones 01/2014; 95:269-98. DOI:10.1016/B978-0-12-800174-5.00011-9 · 1.78 Impact Factor
Show more