Repression of Human<i>GSTA1</i>by Interleukin-1β Is Mediated by Variant Hepatic Nuclear Factor-1C

Ng, Lorraine; Nichols, Kathleen D.; O'Rourke, Kelly; Maslen, Ann; Kirby, Gordon M.

doi:10.1124/mol.106.028563

Cited by 12 publications

(5 citation statements)

References 28 publications

(41 reference statements)

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“…Our results are in agreement with other observations indicating that NO-Derived Oxidants inhibit GST expression (Wong et al 2001). The transcriptional suppression of GST by IL-1β is known to be mediated by hepatic nuclear factor [Ng et al, 2007]. Furthermore, our findings strongly suggest that GST inactivation after IL-1β addition could be attributed, in part, to NO generation.…”

Section: Discussionsupporting

confidence: 93%

492 Selective Inhibition of Inducible Nitric Oxide Synthase Prevents Lipid Peroxidation in Cartilage From Patients With Osteoarthritis

Bentz¹,

Zaouter²,

Osman³

et al. 2011

Osteoarthritis and Cartilage

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INTRODUCTION:Emerging evidence indicates that nitric oxide (NO), which is increased in osteoarthritic (OA) cartilage, plays a role in 4-hydroxynonenal (HNE) generation through peroxynitrite formation. HNE is considered as the most reactive product of lipid peroxidation (LPO). We have previously reported that HNE levels in synovial fluids are more elevated in knees of OA patients compared to healthy individuals. We also demonstrated that HNE induces a panoply of inflammatory and catabolic mediators known for their implication in OA cartilage degradation. The aim of the present study was to investigate the ability of inducible NO synthase (iNOS) inhibitor, L-NIL (L-N6-(L-Iminoethyl)Lysine), to prevent HNE generation through NO inhibition in human OA chondrocytes.METHOD: Cells and cartilage explants were treated with or without either an NO generator (SIN or interleukin 1beta (IL-1β)) or HNE in absence or presence of L-NIL. Protein expression of both iNOS and free-radical-generating NOX subunit p47 (phox) were investigated by western blot. iNOS mRNA detection was measured by real-time RT-PCR. HNE production was analysed by ELISA, Western blot and immunohistochemistry. S-nitrosylated proteins were evaluated by Western Blot. Prostaglandin E2 (PGE2) and metalloproteinase 13 (MMP-13) levels as well as glutathione S-transferase (GST) activity were each assessed with commercial kits. NO release was determined using improved Griess method. Reactive oxygen species (ROS) generation was revealed using fluorescent microscopy with the use of commercial kits.RESULTS: L-NIL prevented IL-1β-induced NO release, iNOS expression at protein and mRNA levels, S-nitrosylated proteins and HNE in a dose dependent manner after 24h of incubation. Interestingly, we revealed that L-NIL abolished IL-1β-induced NOX component p47phox as well as ROS release. The HNE-induced PGE2 release and both cyclooxygenase-2 (COX-2) and MMP-13 expression were significantly reduced by L-NIL addition. Furthermore, L-NIL blocked the IL-1β induced inactivation of GST, an HNE-metabolizing enzyme. Also, L-NIL prevented HNE induced cell death at cytotoxic levels. CONCLUSION:Altogether, our findings support a beneficial effect of L-NIL in OA by preventing LPO process in NO-dependent and/or independent mechanisms.

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Section: Discussionsupporting

confidence: 93%

492 Selective Inhibition of Inducible Nitric Oxide Synthase Prevents Lipid Peroxidation in Cartilage From Patients With Osteoarthritis

Bentz¹,

Zaouter²,

Osman³

et al. 2011

Osteoarthritis and Cartilage

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“…More relevant to our study is the marked up-regulation of GSTA1 expression during differentiation of postconfluent Caco-2 cells [14], [30], [31]. This finding supports the results of a study by Scharmach et al, 2009 that demonstrated marked induction of GSTA1, GSTA2 and to a lesser extent GSTA3 in association with Caco-2 cell differentiation whereas constant high expression was observed for GSTP1 and GSTO1, marginal expression for GSTA4, GSTT2 and GSTZ1 and no expression of GSTM5 and GSTT1 [30].…”

Section: Discussionmentioning

confidence: 91%

Low Levels of GSTA1 Expression Are Required for Caco-2 Cell Proliferation

et al. 2012

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The colonic epithelium continuously regenerates with transitions through various cellular phases including proliferation, differentiation and cell death via apoptosis. Human colonic adenocarcinoma (Caco-2) cells in culture undergo spontaneous differentiation into mature enterocytes in association with progressive increases in expression of glutathione S-transferase alpha-1 (GSTA1). We hypothesize that GSTA1 plays a functional role in controlling proliferation, differentiation and apoptosis in Caco-2 cells. We demonstrate increased GSTA1 levels associated with decreased proliferation and increased expression of differentiation markers alkaline phosphatase, villin, dipeptidyl peptidase-4 and E-cadherin in postconfluent Caco-2 cells. Results of MTS assays, BrdU incorporation and flow cytometry indicate that forced expression of GSTA1 significantly reduces cellular proliferation and siRNA-mediated down-regulation of GSTA1 significantly increases cells in S-phase and associated cell proliferation. Sodium butyrate (NaB) at a concentration of 1 mM reduces Caco-2 cell proliferation, increases differentiation and increases GSTA1 activity 4-fold by 72 hours. In contrast, 10 mM NaB causes significant toxicity in preconfluent cells via apoptosis through caspase-3 activation with reduced GSTA1 activity. However, GSTA1 down-regulation by siRNA does not alter NaB-induced differentiation or apoptosis in Caco-2 cells. While 10 mM NaB causes GSTA1-JNK complex dissociation, phosphorylation of JNK is not altered. These findings suggest that GSTA1 levels may play a role in modulating enterocyte proliferation but do not influence differentiation or apoptosis.

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“…Furthermore, busulfan‐induced steatosis might occur only in patients with high hepatic GSTA1 expression, as the one found in the female patient whose liver tumor was used for the isolation of the HepaRG cell line [19]. Notably, various factors can significantly modulate GSTA1 expression including genetic polymorphism [64], hormones [65], and cytokines [66]. Whether high GSTA1 expression is uncommon in the general population would require further investigations.…”

Section: Discussionmentioning

confidence: 99%

Busulfan induces steatosis in HepaRG cells but not in primary human hepatocytes: Possible explanations and implication for the prediction of drug‐induced liver injury

Allard,

Bucher,

Ferron

et al. 2023

Fundamemntal Clinical Pharma

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BackgroundThe antineoplastic drug busulfan can induce different hepatic lesions including cholestasis and sinusoidal obstruction syndrome. However, hepatic steatosis has never been reported in patients.ObjectivesThis study aimed to determine whether busulfan could induce steatosis in primary human hepatocytes (PHH) and differentiated HepaRG cells.MethodsNeutral lipids were determined in PHH and HepaRG cells. Mechanistic investigations were performed in HepaRG cells by measuring metabolic fluxes linked to lipid homeostasis, reduced glutathione (GSH) levels, and expression of genes involved in lipid metabolism and endoplasmic reticulum (ER) stress. Analysis of two previous transcriptomic datasets was carried out.ResultsBusulfan induced lipid accumulation in HepaRG cells but not in six different batches of PHH. In HepaRG cells, busulfan impaired VLDL secretion, increased fatty acid uptake, and induced ER stress. Transcriptomic data analysis and decreased GSH levels suggested that busulfan‐induced steatosis might be linked to the high expression of glutathione S‐transferase (GST) isoenzyme A1, which is responsible for the formation of the hepatotoxic sulfonium cation conjugate. In keeping with this, the GST inhibitor ethacrynic acid and the chemical chaperone tauroursodeoxycholic acid alleviated busulfan‐induced lipid accumulation in HepaRG cells supporting the role of the sulfonium cation conjugate and ER stress in steatosis.ConclusionWhile the HepaRG cell line is an invaluable tool for pharmacotoxicological studies, it might not be always an appropriate model to predict and mechanistically investigate drug‐induced liver injury. Hence, we recommend carrying out toxicological investigations in both HepaRG cells and PHH to avoid drawing wrong conclusions on the potential hepatotoxicity of drugs and other xenobiotics.

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Repression of HumanGSTA1by Interleukin-1β Is Mediated by Variant Hepatic Nuclear Factor-1C

Cited by 12 publications

References 28 publications

492 Selective Inhibition of Inducible Nitric Oxide Synthase Prevents Lipid Peroxidation in Cartilage From Patients With Osteoarthritis

492 Selective Inhibition of Inducible Nitric Oxide Synthase Prevents Lipid Peroxidation in Cartilage From Patients With Osteoarthritis

Low Levels of GSTA1 Expression Are Required for Caco-2 Cell Proliferation

Busulfan induces steatosis in HepaRG cells but not in primary human hepatocytes: Possible explanations and implication for the prediction of drug‐induced liver injury

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