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Deficiency in the nuclear factor E2-related factor 2 renders pancreatic ?-cells vulnerable to arsenic-induced cell damage.

ABSTRACT: Chronic human exposure to inorganic arsenic (iAs), a potent environmental oxidative stressor, is associated with increased prevalence of type 2 diabetes, where impairment of pancreatic ?-cell function is a key pathogenic factor. Nuclear factor E2-related factor 2 (Nrf2) is a central transcription factor regulating cellular adaptive response to oxidative stress. However, persistent activation of Nrf2 in response to chronic oxidative stress, including inorganic arsenite (iAs³?) exposure, blunts glucose-triggered reactive oxygen species (ROS) signaling and impairs glucose-stimulated insulin secretion (GSIS). In the current study, we found that MIN6 pancreatic ?-cells with stable knockdown of Nrf2 (Nrf2-KD) by lentiviral shRNA and pancreatic islets isolated from Nrf2-knockout (Nrf2?/?) mice exhibited reduced expression of several antioxidant and detoxification enzymes in response to acute iAs³? exposure. As a result, Nrf2-KD MIN6 cells and Nrf2?/? islets were more susceptible to iAs³? and monomethylarsonous acid (MMA³?)-induced cell damage, as measured by decreased cell viability, augmented apoptosis and morphological change. Pretreatment of MIN6 cells with Nrf2 activator tert-butylhydroquinone protected the cells from iAs³?-induced cell damage in an Nrf2-dependent fashion. In contrast, antioxidant N-acetyl cysteine protected Nrf2-KD MIN6 cells against acute cytotoxicity of iAs³?. The present study demonstrates that Nrf2-mediated antioxidant response is critical in the pancreatic ?-cell defense mechanism against acute cytotoxicity by arsenic. The findings here, combined with our previous results on the inhibitory effect of antioxidants on ROS signaling and GSIS, suggest that Nrf2 plays paradoxical roles in pancreatic ?-cell dysfunction induced by environmental arsenic exposure.

SUBMITTER: Yang B

PROVIDER: S-EPMC3478490 | biostudies-other | 2012 Nov

REPOSITORIES: biostudies-other

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Deficiency in the nuclear factor E2-related factor 2 renders pancreatic β-cells vulnerable to arsenic-induced cell damage.

Yang Bei B Fu Jingqi J Zheng Hongzhi H Xue Peng P Yarborough Kathy K Woods Courtney G CG Hou Yongyong Y Zhang Qiang Q Andersen Melvin E ME Pi Jingbo J

Toxicology and applied pharmacology 20120921 3

Chronic human exposure to inorganic arsenic (iAs), a potent environmental oxidative stressor, is associated with increased prevalence of type 2 diabetes, where impairment of pancreatic β-cell function is a key pathogenic factor. Nuclear factor E2-related factor 2 (Nrf2) is a central transcription factor regulating cellular adaptive response to oxidative stress. However, persistent activation of Nrf2 in response to chronic oxidative stress, including inorganic arsenite (iAs³⁺) exposure, blunts gl ...[more]

PMID: 23000044

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Project description:Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor known to induce the expression of a variety of antioxidant and detoxification genes. Recently, increasing evidence has revealed roles for Nrf2 in glucose, lipid, and energy metabolism; however, the exact functions of Nrf2 in hepatocyte biology are largely unclear. In the current study, the transient knockdown of Nrf2 via siRNA transfection enhanced the glucose uptake of fasting AML12 hepatocytes to 325.3?±?11.1% ( P?<?0.05) of that of untransfected control cells. The impacts of Nrf2 knockdown (NK) on the antioxidant system, inflammatory response, and glucose metabolism were then examined in AML12 cells under both high-glucose (33?mmol/L) and low-glucose (4.5?mmol/L) conditions. NK lowered the gene and protein expression of the anti-oxidases heme oxygenase-1 and NAD(P)H: quinone oxidoreductase 1 and increased p-eukaryotic initiation factor-2?S51, p-nuclear factor-?B p65S276, and its downstream proinflammatory factors, including interleukin-1 beta, tumor necrosis factor-?, matrix metalloproteinase 2, and matrix metalloproteinase 9, at the protein level. NK also altered the protein expression of fibroblast growth factor 21, glucose transporter type 4, insulin-like growth factor 1, forkhead box protein O1, p-AKTS473, and p-GSK3?/?Y279/Y216, which are involved in glucose uptake, glycogenesis, and gluconeogenesis in AML12 cells. Our results provide a comprehensive understanding of the central role of Nrf2 in the regulation of glucose metabolism in AML12 hepatocytes, in addition to its classical roles in the regulation of redox signaling, endoplasmic reticulum stress and proinflammatory responses, and support the potential of Nrf2 as a therapeutic target for the prevention and treatment of obesity and other associated metabolic syndromes. Impact statement Increasing evidence supports the complexity of Nrf2 functions beyond the antioxidant and detoxification response. Previous in vivo studies employing either Nrf2-knockout or Nrf2-activated mice have achieved a similar endpoint: protection against an obese and insulin-resistant phenotype that includes impaired lipogenesis and gluconeogenesis in the liver. These apparently paradoxical observations led us to evaluate the impact of Nrf2 in liver cells in the absence of any influence from the systemic environment, including changes in the secretion of adipokines and proinflammatory cytokines by adipose tissues. In the present study, Nrf2 knockdown was sufficient to induce fundamental changes in the glucose metabolism of AML12 hepatocytes in addition to its classical cytoprotective functions. We also discuss similarities and differences between our in vitro study and previous in vivo studies, which may be helpful to dissect and better understand in vivo data that represents the culmination of both local and systemic alterations.

Dataset Information

Deficiency in the nuclear factor E2-related factor 2 renders pancreatic ?-cells vulnerable to arsenic-induced cell damage.

Publications

Deficiency in the nuclear factor E2-related factor 2 renders pancreatic β-cells vulnerable to arsenic-induced cell damage.

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