Grp78 Heterozygosity Promotes Adaptive Unfolded Protein Response and Attenuates Diet-Induced Obesity and Insulin Resistance

Department of Biochemistry and Molecular Biology, University of Southern California/Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
Diabetes (Impact Factor: 8.1). 10/2009; 59(1):6-16. DOI: 10.2337/db09-0755
Source: PubMed


To investigate the role of the endoplasmic reticulum (ER) chaperone glucose-regulated protein (GRP) 78/BiP in the pathogenesis of obesity, insulin resistance, and type 2 diabetes.
Male Grp78(+/-) mice and their wild-type littermates were subjected to a high-fat diet (HFD) regimen. Pathogenesis of obesity and type 2 diabetes was examined by multiple approaches of metabolic phenotyping. Tissue-specific insulin sensitivity was analyzed by hyperinsulinemic-euglycemic clamps. Molecular mechanism was explored via immunoblotting and tissue culture manipulation.
Grp78 heterozygosity increases energy expenditure and attenuates HFD-induced obesity. Grp78(+/-) mice are resistant to diet-induced hyperinsulinemia, liver steatosis, white adipose tissue (WAT) inflammation, and hyperglycemia. Hyperinsulinemic-euglycemic clamp studies revealed that Grp78 heterozygosity improves glucose metabolism independent of adiposity and following an HFD increases insulin sensitivity predominantly in WAT. As mechanistic explanations, Grp78 heterozygosity in WAT under HFD stress promotes adaptive unfolded protein response (UPR), attenuates translational block, and upregulates ER degradation-enhancing alpha-mannosidase-like protein (EDEM) and ER chaperones, thus improving ER quality control and folding capacity. Further, overexpression of the active form of ATF6 induces protective UPR and improves insulin signaling upon ER stress.
HFD-induced obesity and type 2 diabetes are improved in Grp78(+/-) mice. Adaptive UPR in WAT could contribute to this improvement, linking ER homeostasis to energy balance and glucose metabolism.

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    • "Several genetic strategies have been applied to tease out the roles of ER stress and chaperones in liver steatosis. The ER chaperone protein GRP78 is a critical regulator of ER homeostasis and stress responses, because it interacts and sequesters all major UPR sensors (Ye et al., 2010; Pfaffenbach and Lee, 2011). Kammoun et al. (2009) found that overexpression of GRP78 inhibited ER stress-induced sterol regulatory element binding protein (SREBP) expression and steatosis in the livers of obese (ob/ob) mice. "
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    ABSTRACT: As an adaptive response to the overloading with misfolded proteins in the endoplasmic reticulum (ER), ER stress plays critical roles in maintaining protein homeostasis in the secretory pathway to avoid damage to the host. Such a conserved mechanism is accomplished through three well-orchestrated pathways known collectively as unfolded protein response (UPR). Persistent and pathological ER stress has been implicated in a variety of diseases in metabolic, inflammatory, and malignant conditions. Furthermore, ER stress is directly linked with inflammation through UPR pathways, which modulate transcriptional programs to induce the expression of inflammatory genes. Importantly, the inflammation induced by ER stress is directly responsible for the pathogenesis of metabolic and inflammatory diseases. In this review, we will discuss the potential signaling pathways connecting ER stress with inflammation. We will also depict the interplay between ER stress and inflammation in the pathogenesis of hepatic steatosis, inflammatory bowel diseases and colitis-associated colon cancer.
    Frontiers in Genetics 07/2014; 5:242. DOI:10.3389/fgene.2014.00242
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    • "Our study confirmed the existence of glucotoxic effects on INS-1 cell survival and secretory function and also demonstrated that the deleterious effects of high glucose were additive to those of PSCs. One important mechanism of β-cell failure in T2DM is the development of ER stress as a response to an imbalance between the rate of protein synthesis and folding capacity of the endoplasmic reticulum in hypersecreting β-cells, eventually resulting in β-cell apoptosis [37, 38]. Our measurements of increased CHOP mRNA and protein levels in response to PSCs-CM and/or high glucose suggest that the detrimental effects of PSCs on β-cells may be associated with the activation of the ER stress response. "
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    ABSTRACT: Background and Aims. We here assess the effects of PSCs on β-cell function and apoptosis in vivo and in vitro. Materials and Methods. PSCs were transplanted into Wistar and Goto-Kakizaki (GK) rats. Sixteen weeks after transplantation, β-cell function, apoptosis, and islet fibrosis were assessed. In vitro the effects of PSCs conditioned medium (PSCs-CM) and/or high concentration of glucose on INS-1 cell function was assessed by measuring insulin secretion, INS-1 cell survival, apoptosis, and endoplasmic reticulum stress (ER stress) associated CHOP expression. Results. PSCs transplantation exacerbated the impaired β-cell function in GK rats, but had no significant effects in Wistar rats. In vitro, PSCs-CM caused impaired INS-1 cell viability and insulin secretion and increased apoptosis, which were more pronounced in the presence of high glucose. Conclusion. Our study demonstrates that PSCs induce β-cell failure in vitro and in vivo.
    International Journal of Endocrinology 07/2014; 2014:165612. DOI:10.1155/2014/165612 · 1.95 Impact Factor
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    • "Markers of UPR activation have been detected in FLD samples from multiple species (Imrie and Sadler, 2012; Malhi and Kaufman, 2011) and inducing ER stress with Tm is sufficient to cause FLD in mice (Lee et al., 2012; Rutkowski et al., 2008; Teske et al., 2011; Wu et al., 2007; Yamamoto et al., 2010; Zhang et al., 2011) and zebrafish (Cinaroglu et al., 2011; Thakur et al., 2011). Moreover, steatosis can be influenced by altering the expression of key UPR mediators, including BiP (Ji et al., 2011; Kammoun et al., 2009; Ye et al., 2010), PERK (Teske et al., 2011), IRE1A/XBP1 (Lee et al., 2008; Ozcan et al., 2006; Zhang et al., 2011) and ATF6 (Cinaroglu et al., 2011; Howarth et al., 2014; Rutkowski et al., 2008; Wu et al., 2007; Yamamoto et al., 2010). Our recent finding that Atf6 overexpression is sufficient to cause steatosis in zebrafish (Howarth et al., 2014) definitively shows that activation of this pathway is a culprit in FLD. "
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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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