FOXO1 involvement in insulin resistance-related pro-inflammatory cytokine production in hepatocytes

Miao, Hongming; Zhang, Yang; Lu, Zhongyan; Liu, Qin; Gan, Lixia

doi:10.1007/s00011-011-0417-3

Cited by 33 publications

(26 citation statements)

References 45 publications

(62 reference statements)

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“…This observation is even more surprising as dexamethasone increased the expression of Foxo1, confirming a previous study with INS-1 cells showing that dexamethasone increases, while prolactin decreases, the transcript levels of Foxo1 [27]. Increased protein levels in combination with reduced phosphorylation and activation of FOXO1 after dexamethasone exposure has been described in a variety of cells, including hepatocytes, cardiomyocytes and tenocytes [28][29][30]. Interestingly, in tenocytes, dexamethasone-mediated inhibition of FOXO1 phosphorylation was counteracted by insulin.…”

Section: Discussionsupporting

confidence: 83%

Regulation of forkhead box O1 (FOXO1) by protein kinase B and glucocorticoids: different mechanisms of induction of beta cell death in vitro

et al. 2013

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Aims/hypothesis In steroid diabetes insulin secretion does not adequately compensate for enhanced hepatic gluconeogenesis and peripheral insulin resistance. Previous studies suggest that activation of the transcription factor forkhead box O1 (FOXO1) contributes to glucocorticoid-induced beta cell death. This study examines the role and regulation of FOXO1 in insulin-secreting cells.Methods INS-1E cells and mouse islet cells were cultured in the presence of dexamethasone. Signalling pathways were modified pharmacologically or by small interfering (si) RNA-mediated inhibition of protein synthesis. Changes in protein abundance and phosphorylation were analysed by western blotting, and subcellular localisation was assessed using confocal microscopy. Transcript levels were examined by RT-PCR.Results Surprisingly, downregulation of FOXO1 by siRNA did not affect dexamethasone-induced apoptosis or Bim expression, but it prevented the effects of the pan protein kinase B (AKT) inhibitor (Akti-1/2). Indeed, dexamethasone and Akti-1/2 synergistically increased beta cell death and Bim expression. Akti-1/2 triggered dephosphorylation and nuclear translocation of FOXO1. Glucocorticoidreceptor activation stimulated Foxo1 transcription, but FOXO1 phosphorylation was unchanged and the cytosolic concentration of FOXO1 remained high in relation to its nuclear concentration. However, subcellular fractionation revealed a significant increase in both cytosolic and nuclear FOXO1 compared with untreated cells. Dexamethasone diminished Pdx1 mRNA level, an effect which was not reversed by siRNA against Foxo1. Downregulation of AKT isoforms and serum/glucocorticoid-regulated kinase 1 (SGK1) suggests that only sustained suppression of all three AKT isoforms caused dephosphorylation and nuclear accumulation of FOXO1. Conclusions/interpretation This study reveals that FOXO1 is not the main mediator of glucocorticoidreceptor-induced beta cell apoptosis, but rather that it escalates beta cell death when AKT activity is inhibited by distinct pathways.

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Section: Discussionsupporting

confidence: 83%

Regulation of forkhead box O1 (FOXO1) by protein kinase B and glucocorticoids: different mechanisms of induction of beta cell death in vitro

et al. 2013

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“…In addition, the induction of active chromatin states by FOXO1 has been described in a previous study (18). Insulin has the ability to negatively regulate the expression and transcriptional activity of FOXO1 (24,25). FOXO1 has been reported to confer an inhibitory effect of insulin on gene transcription through binding to the IRE in the promoter sequences of target genes (26).…”

Section: Discussionmentioning

confidence: 82%

FOXO1-mediated epigenetic modifications are involved in the insulin-mediated repression of hepatocyte aquaporin 9 expression

Qiu

Lü

et al. 2014

Molecular Medicine Reports

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Abstract. Aquaporin (AQP) 9 transports glycerol and water, and belongs to the aquaglyceroporin subfamily. Insulin acts as a negative regulator of AQP9, and FOXO1 has the ability to mediate the regulatory effects of insulin on target gene expression. The aim of the present study was to determine whether insulin-induced repression of AQP9 involved an epigenetic mechanism. HepG2 human hepatocyte cells were treated with 500 µM insulin for different durations. AQP9 mRNA expression levels were determined by quantitative polymerase chain reaction (qPCR), and histone H3 acetylation, phosphorylation and methylation at the insulin responsive element (IRE) of the AQP9 promoter was assessed using chromatin immunoprecipitation coupled with qPCR. The effects of lentiviral FOXO1 overexpression on AQP9 expression levels and H3 modifications at the AQP9 promoter were also determined. The insulin treatment resulted in a significant and time-dependent reduction in AQP9 mRNA expression levels in HepG2 cells, as compared with untreated cells (P<0.05). In the insulin-treated cells, the levels of H3 acetylation and phosphorylation were significantly reduced (P<0.05), but the level of H3 methylation was increased. Enforced expression of FOXO1 increased AQP9 mRNA and protein expression levels in HepG2 cells. Furthermore, FOXO1 overexpression promoted H3 acetylation and phosphorylation, and reduced H3 methylation at the IRE locus of the AQP9 promoter. These data provide, to the best of our knowledge, the first evidence that insulin-induced transcriptional suppression of AQP9 expression in hepatocytes involves FOXO1-mediated H3 modifications at the IRE locus in the promoter. IntroductionAquaporins (AQPs) are a family of ubiquitous membrane proteins that form pores for the selective permeation of water and other small molecules (1). Aquaglyceroporins belong to a subgroup of the AQP family and are able to transport small organic compounds, such as glycerol or urea. Overall, five molecules (AQP3, AQP7, AQP9, AQP10 and bacterial glycerol facilitator) have been classified as aquaglyceroporins (2). AQP9 is most abundantly expressed in the liver (3). Rojek et al (4) reported that AQP9 knockout mice exhibit hypertriacylglycerolemia, a sign of metabolic syndrome. AQP9 is implicated in hepatic glycerol transport and consequently contributes to neoglucogenesis (5). Therefore, the dysregulation of AQP9 gene expression is important in the pathogenesis of metabolic disorders.Compelling evidence has indicated that insulin acts as a key regulator of AQP9 (6,7). The AQP9 promoter contains a negative insulin response element (IRE), TGTTTTC, at -496/-502 and AQP9 mRNA expression is downregulated by insulin in cultured hepatocytes (6). Rodríguez et al (8) observed that insulin inhibited the expression of AQP9 via the PI3K/Akt/mTOR signaling pathway. In a rat model, hepatic AQP9 expression levels were found to fluctuate with circulating insulin levels (9). Forkhead box protein O1 (FOXO1) is a forkhead transcriptional factor that mediates the regulatory effect...

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“…We demonstrated that CGI-58 deficiency-induced IL-1β transcription via activating a transcriptional factor forkhead box-containing protein O subfamily-1 (FOXO1) [9] , which was previously reported to involve in multiple proinflammatory cytokine production in hepatocytes, adipocytes and macrophages by us [10][11] and others [12][13][14] . In further studies, we verified that CGI-58/inflammasome pathway-mediated IL-1β secretion stimulates the expression of suppressor of cytokine signaling 3 (SOCS3), which dampens insulin signaling in macrophages [9] .…”

Section: Research Highlightmentioning

confidence: 81%

“…In further studies, we verified that CGI-58/inflammasome pathway-mediated IL-1β secretion stimulates the expression of suppressor of cytokine signaling 3 (SOCS3), which dampens insulin signaling in macrophages [9] . The impaired insulin signaling activates FOXO1 activity by decreasing FOXO1 phosphorylation [9][10][11] . Thus, CGI-58 deficiency activates NLRP3-inflammasome pathway to initiate a vicious cycle (IL-1β -SOCS3 -FOXO1 -IL-1β) (Figure 1).…”

Section: Research Highlightmentioning

confidence: 99%

Macrophage CGI-58/IL-1β pathway prevents overnutrition-induced chronic inflammation and insulin resistance

Miao

Yu²,

Liang³

2015

Macrophage

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Proinflammatory activation of macrophages is causally linked to obesity-related chronic inflammation and insulin resistance (IR). However, the metabolic factors mediating macrophage activation in response to overnutrition is not fully understood. We identified comparative gene identification-58 (CGI-58), a well characterized lipolytic co-activator of adipose triglyceride lipase, as a novel suppressor of proinflammatory cytokine production in macrophages. Specifically, in response to overnutrition, macrophage CGI-58 deficiency activates NLRP3-inflammasome pathway to initiate a vicious cycle (IL-1β-SOCS3-FOXO1-IL-1β), which further induces systemic chronic inflammation and IR.

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FOXO1 involvement in insulin resistance-related pro-inflammatory cytokine production in hepatocytes

Abstract: FOXO1 potentiates pro-inflammatory cytokine production in insulin-resistant hepatocytes.

Cited by 33 publications

References 45 publications

Regulation of forkhead box O1 (FOXO1) by protein kinase B and glucocorticoids: different mechanisms of induction of beta cell death in vitro

Regulation of forkhead box O1 (FOXO1) by protein kinase B and glucocorticoids: different mechanisms of induction of beta cell death in vitro

FOXO1-mediated epigenetic modifications are involved in the insulin-mediated repression of hepatocyte aquaporin 9 expression

Macrophage CGI-58/IL-1β pathway prevents overnutrition-induced chronic inflammation and insulin resistance

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