Nrf2 activation diminishes during adipocyte differentiation of ST2 cells

Habeos, Ioannis

doi:10.3892/ijmm.2011.761

Cited by 12 publications

(10 citation statements)

References 38 publications

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“… 45 The protein level of nuclear Nrf2 also continuously decreases during adipogenic differentiation in ST2 cells, a bone marrow-derived MSC cell line. 46 This expression pattern is required for normal adipocyte differentiation of 3T3L1 cells and is associated with increased oxidative stress levels that can facilitate differentiation processes. 47 SFN can also suppress the adipogenic differentiation of 3T3L1 cells.…”

Section: Discussionmentioning

confidence: 99%

Cellular localization of NRF2 determines the self-renewal and osteogenic differentiation potential of human MSCs via the P53–SIRT1 axis

2016

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NRF2 (nuclear factor erythroid-derived 2-like 2) plays an important role in defense against oxidative stress at the cellular level. Recently, the roles of NRF2 in embryonic and adult stem cells have been reported, but its role in maintaining self-renewal and differentiation potential remains unknown. We studied the mechanisms of NRF2 action in mesenchymal stem cells (MSCs) derived from human bone marrow. We found that the cellular localization of NRF2 changed during prolonged cell passage and osteogenic differentiation. Blocking the nuclear import of NRF2 using ochratoxin A (OTA) induced the loss of the self-renewal and osteogenic potential of early-passage (EP) MSCs. Conversely, reinforcing the nuclear import of NRF2 using tert-butylhydroquinone (t-BHQ) improved the self-renewal capacity and maintained the differentiation potential in the osteogenic lineage of EP MSCs. Real-time quantitative PCR and western blot analysis showed that NRF2 positively regulates sirtuin 1 (SIRT1) at the mRNA and protein levels via the negative regulation of p53. The self-renewal and osteogenic potential suppressed in OTA-treated or NRF2-targeting small hairpin RNA (shRNA)-infected EP MSCs were rescued by introducing small interfering RNA (siRNA) targeting p53. t-BHQ treatment in late-passage (LP) MSCs, which lost their self-renewal and osteogenic potential, reversed these effects. In LP MSCs treated with t-BHQ for ∼7 days, the phosphorylation and nuclear localization of NRF2 improved and SIRT1 protein level increased, whereas p53 protein levels decreased. Therefore, our results suggest that NRF2 plays an important role in regulating p53 and SIRT1 to maintain MSC stemness. This study is the first to establish a functional link between NRF2 and SIRT1 expression in the maintenance of MSC self-renewal and differentiation potential.

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Section: Discussionmentioning

confidence: 99%

Cellular localization of NRF2 determines the self-renewal and osteogenic differentiation potential of human MSCs via the P53–SIRT1 axis

2016

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“…Of note, the differentiation of osteoblasts and adipocytes is tightly regulated and both cell types originate from a common progenitor. Using a cell culture model, Chartoumpekis et al [56] demonstrated that during adipocyte differentiation, Nrf2 activation is decreased. This indirectly supports our finding that upon Nrf2 deletion, osteoblast differentiation was decreased.…”

Section: Discussionmentioning

confidence: 99%

Loss of Nrf2 accelerates ionizing radiation-induced bone loss by upregulating RANKL

Rana¹,

Schultz²,

Freeman

et al. 2012

Free Radical Biology and Medicine

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Radiation therapy is an integral part of treatment for cancer patients; however, major side effects of this modality include aberrant bone remodeling and bone loss. Ionizing radiation (IR) is a major external factor that contributes to a significant increase in oxidative stress such as reactive oxygen species (ROS), has been implicated in osteoporotic phenotypes, and has been implicated in osteoporotic phenotypes, bone loss, and fracture risk. One of the major cellular defenses against heightened oxidative stress is mediated by nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a master transcription factor that regulates induction of antioxidant gene expression and phase II antioxidant enzymes. Our objective was to test the hypothesis that loss of functional Nrf2 increases radiation-induced bone loss. We irradiated (single dose, 20 Gy) the hindlegs of age- and sex-matched Nrf2+/+ and Nrf2−/− mice. After 1 month, microCT analysis and histology revealed a drastic overall decrease in the bone volume after irradiation of mice lacking Nrf2. Although radiation exposure led to bone loss in mice with intact Nrf2, it was dramatically enhanced by loss of Nrf2. Furthermore, in the absence of Nrf2, a decrease in osteoblast mineralization was noted in calvarial osteoblasts compared with wild-type controls, and treatment with a common antioxidant, N-acetyl-l-cysteine (NAC), was able to rescue the mineralization. As expected, we observed a higher number of osteoclasts in Nrf2−/− mice compared to Nrf2+/+ mice, and after irradiation, the trend remained the same. RT-PCR analysis of calvarial osteoblasts revealed that in the absence of Nrf2, the expression of RANKL was increased after irradiation. Interestingly, RANKL expression was suppressed when the calvarial osteoblasts were treated with NAC before IR exposure. Taken together, our data suggest that loss of Nrf2 leads to heightened oxidative stress and increased susceptibility to radiation-induced bone loss.

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“…In contrast, Chartoumpekis et al . observed lower NRF2 abundance in the nucleus during adipogenesis, which they hypothesized could lead to the higher ROS levels needed for the differentiation process [125]. …”

Section: Ros Response Mechanisms: Transcription Factorsmentioning

confidence: 99%

Genetics of Oxidative Stress in Obesity

Rupérez

Gil

Aguilera

2014

IJMS

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Obesity is a multifactorial disease characterized by the excessive accumulation of fat in adipose tissue and peripheral organs. Its derived metabolic complications are mediated by the associated oxidative stress, inflammation and hypoxia. Oxidative stress is due to the excessive production of reactive oxygen species or diminished antioxidant defenses. Genetic variants, such as single nucleotide polymorphisms in antioxidant defense system genes, could alter the efficacy of these enzymes and, ultimately, the risk of obesity; thus, studies investigating the role of genetic variations in genes related to oxidative stress could be useful for better understanding the etiology of obesity and its metabolic complications. The lack of existing literature reviews in this field encouraged us to gather the findings from studies focusing on the impact of single nucleotide polymorphisms in antioxidant enzymes, oxidative stress-producing systems and transcription factor genes concerning their association with obesity risk and its phenotypes. In the future, the characterization of these single nucleotide polymorphisms (SNPs) in obese patients could contribute to the development of controlled antioxidant therapies potentially beneficial for the treatment of obesity-derived metabolic complications.

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Nrf2 activation diminishes during adipocyte differentiation of ST2 cells

Cited by 12 publications

References 38 publications

Cellular localization of NRF2 determines the self-renewal and osteogenic differentiation potential of human MSCs via the P53–SIRT1 axis

Cellular localization of NRF2 determines the self-renewal and osteogenic differentiation potential of human MSCs via the P53–SIRT1 axis

Loss of Nrf2 accelerates ionizing radiation-induced bone loss by upregulating RANKL

Genetics of Oxidative Stress in Obesity

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