Article

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.

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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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    • "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). "
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    • "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. "
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