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: 13.22). 10/2008; 118(10):3378-89. DOI: 10.1172/JCI34587
Source: PubMed


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.

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Available from: Randal J Kaufman, Oct 04, 2015
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    • "Several lines of evidence have demonstrated that CHOP is considerably elevated in islet beta cells of mice with type 2 diabetes [3]. Moreover, a remarkable decrease of beta cell apoptosis was exhibited in CHOP-deficient db/db mice, which further confirmed that CHOP mediates beta cell apoptosis during ER stress [7]. However, since CHOP was not the final executor of apoptosis, the pro-apoptotic effect of CHOP seemed to be mainly mediated by its downstream targets. "
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    ABSTRACT: Aims Vildagliptin promotes beta cell survival by inhibiting cell apoptosis. It has been suggested that chronic ER (endoplasmic reticulum) stress triggers beta cell apoptosis. The objective of the study is to explore whether the pro-survival effect of vildagliptin is associated with attenuation of endoplasmic reticulum stress in islets of db/db mice. Methods Vildagliptin was orally administered to db/db mice for 6 weeks, followed by evaluation of beta cell apoptosis by caspase3 activity and TUNEL staining method. Endoplasmic reticulum stress markers were determined with quantitative RT-PCR, immunohistochemistry and immunoblot analysis. Results After 6 weeks of treatment, vildagliptin treatment increased plasma active GLP-1 levels (22.63 ± 1.19 vs. 11.69 ± 0.44, P < 0.001), inhibited beta cell apoptosis as demonstrated by lower amounts of TUNEL staining nuclei (0.37 ± 0.03 vs. 0.55 ± 0.03, P < 0.01) as well as decreased caspase3 activity (1.48 ± 0.11 vs. 2.67 ± 0.13, P < 0.01) in islets of diabetic mice compared with untreated diabetic group. Further, vildagliptin treatment down-regulated several genes related to endoplasmic reticulum stress including TRIB3 (tribbles homolog 3) (15.9 ± 0.4 vs. 33.3 ± 1.7, × 10− 3, P < 0.001), ATF-4(activating transcription factor 4) (0.83 ± 0.06 vs. 1.42 ± 0.02, P < 0.001) and CHOP(C/EBP homologous protein) (0.07 ± 0.01 vs. 0.16 ± 0.01, P < 0.001). Conclusions Vildagliptin promoted beta cell survival in db/db mice in association with down-regulating markers of endoplasmic reticulum stress including TRIB3, ATF-4 as well as CHOP.
    Metabolism 12/2014; 64(2). DOI:10.1016/j.metabol.2014.08.006 · 3.89 Impact Factor
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    • "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"
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    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 · 3.85 Impact Factor
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    • "Several reports showed that treatment with saturated fatty acids cause numerous alterations that can initiate apoptosis by different mechanisms, including reactive oxygen species, mitochondrial dysfunction, generation of ceramide or induction of CHOP and caspase 3 pathway [9], [13], [39], [40]. In accordance with our results, deletion of CHOP has been shown to enhance beta-cell function and mass in several models of beta-cell stress and T2D [41], [42]. More importantly, this change preceded the induction of cleaved caspase 3, which was apparent after treatment of thapsigargin or high glucose and palmitic acid. "
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    ABSTRACT: In type 2 diabetes, beta-cell dysfunction is thought to be due to several causes, one being the formation of toxic protein aggregates called islet amyloid, formed by accumulations of misfolded human islet amyloid polypeptide (hIAPP). The process of hIAPP misfolding and aggregation is one of the factors that may activate the unfolded protein response (UPR), perturbing endoplasmic reticulum (ER) homeostasis. Molecular chaperones have been described to be important in regulating ER response to ER stress. In the present work, we evaluate the role of chaperones in a stressed cellular model of hIAPP overexpression. A rat pancreatic beta-cell line expressing hIAPP exposed to thapsigargin or treated with high glucose and palmitic acid, both of which are known ER stress inducers, showed an increase in ER stress genes when compared to INS1E cells expressing rat IAPP or INS1E control cells. Treatment with molecular chaperone glucose-regulated protein 78 kDa (GRP78, also known as BiP) or protein disulfite isomerase (PDI), and chemical chaperones taurine-conjugated ursodeoxycholic acid (TUDCA) or 4-phenylbutyrate (PBA), alleviated ER stress and increased insulin secretion in hIAPP-expressing cells. Our results suggest that the overexpression of hIAPP induces a stronger response of ER stress markers. Moreover, endogenous and chemical chaperones are able to ameliorate induced ER stress and increase insulin secretion, suggesting that improving chaperone capacity can play an important role in improving beta-cell function in type 2 diabetes.
    PLoS ONE 07/2014; 9(7):e101797. DOI:10.1371/journal.pone.0101797 · 3.23 Impact Factor
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