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Long isoforms of NRF1 negatively regulate adipogenesis via suppression of PPARγ expression
Nuclear factor erythroid 2-related factor 1 (NRF1), a ubiquitously expressed CNC-bZIP transcription factor, plays a critical role in white adipocyte (WAC) biology, whereas the underlying mechanisms remain unknown. The mouse Nrf1 gene is transcribed in a number of alternatively spliced forms, resulti...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957832/ https://www.ncbi.nlm.nih.gov/pubmed/31931283 http://dx.doi.org/10.1016/j.redox.2019.101414 |
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author | Xue, Peng Hou, Yongyong Zuo, Zhuo Wang, Zhendi Ren, Suping Dong, Jian Fu, Jingqi Wang, Huihui Andersen, Melvin E. Zhang, Qiang Xu, Yuanyuan Pi, Jingbo |
author_facet | Xue, Peng Hou, Yongyong Zuo, Zhuo Wang, Zhendi Ren, Suping Dong, Jian Fu, Jingqi Wang, Huihui Andersen, Melvin E. Zhang, Qiang Xu, Yuanyuan Pi, Jingbo |
author_sort | Xue, Peng |
collection | PubMed |
description | Nuclear factor erythroid 2-related factor 1 (NRF1), a ubiquitously expressed CNC-bZIP transcription factor, plays a critical role in white adipocyte (WAC) biology, whereas the underlying mechanisms remain unknown. The mouse Nrf1 gene is transcribed in a number of alternatively spliced forms, resulting in two long protein isoforms (L-NRF1) containing 741 and 742 amino acids (aa) and multiple short isoforms (S-NRF1). Our previous study found that adipocyte-specific knockout of Nrf1 [Nrf1(f)-KO] in mice disturbs the expression of lipolytic genes in adipocytes, leading to adipocyte hypertrophy followed by inflammation, pyroptosis and insulin resistance. In the present study, we found that the stromal vascular fraction (SVF) cells isolated from white adipose tissues (WAT) of Nrf1(f)-KO mice display augmented adipogenesis showing elevated mRNA and protein expression of adipogenic markers and lipid accumulation. In 3T3-L1 cells, stable knockdown (KD) of all or long isoforms of Nrf1 (termed as A-Nrf1-KD and L-Nrf1-KD, respectively) using lentiviral shRNAs resulted in enhanced and accelerated adipogenic differentiation. Conversely, overexpression of L-NRF1-741, but not any of the S-NRF1, substantially attenuated adipogenesis in 3T3-L1 cells. These findings indicate that L-NRF1 might serve as a critical negative regulator of adipogenesis. Mechanistic investigation revealed that L-NRF1 may negatively regulates the transcription of peroxisome proliferator-activated receptor γ (PPARγ), in particular the master regulator of adipogenesis PPARγ2. Taken all together, the findings in the present study provide further evidence for a novel role of NRF1 beyond its participation in cellular antioxidant response and suggest that L-NRF1 is a negative regulator of PPARγ2 expression and thereby can suppress adipogenesis. |
format | Online Article Text |
id | pubmed-6957832 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-69578322020-01-17 Long isoforms of NRF1 negatively regulate adipogenesis via suppression of PPARγ expression Xue, Peng Hou, Yongyong Zuo, Zhuo Wang, Zhendi Ren, Suping Dong, Jian Fu, Jingqi Wang, Huihui Andersen, Melvin E. Zhang, Qiang Xu, Yuanyuan Pi, Jingbo Redox Biol Research Paper Nuclear factor erythroid 2-related factor 1 (NRF1), a ubiquitously expressed CNC-bZIP transcription factor, plays a critical role in white adipocyte (WAC) biology, whereas the underlying mechanisms remain unknown. The mouse Nrf1 gene is transcribed in a number of alternatively spliced forms, resulting in two long protein isoforms (L-NRF1) containing 741 and 742 amino acids (aa) and multiple short isoforms (S-NRF1). Our previous study found that adipocyte-specific knockout of Nrf1 [Nrf1(f)-KO] in mice disturbs the expression of lipolytic genes in adipocytes, leading to adipocyte hypertrophy followed by inflammation, pyroptosis and insulin resistance. In the present study, we found that the stromal vascular fraction (SVF) cells isolated from white adipose tissues (WAT) of Nrf1(f)-KO mice display augmented adipogenesis showing elevated mRNA and protein expression of adipogenic markers and lipid accumulation. In 3T3-L1 cells, stable knockdown (KD) of all or long isoforms of Nrf1 (termed as A-Nrf1-KD and L-Nrf1-KD, respectively) using lentiviral shRNAs resulted in enhanced and accelerated adipogenic differentiation. Conversely, overexpression of L-NRF1-741, but not any of the S-NRF1, substantially attenuated adipogenesis in 3T3-L1 cells. These findings indicate that L-NRF1 might serve as a critical negative regulator of adipogenesis. Mechanistic investigation revealed that L-NRF1 may negatively regulates the transcription of peroxisome proliferator-activated receptor γ (PPARγ), in particular the master regulator of adipogenesis PPARγ2. Taken all together, the findings in the present study provide further evidence for a novel role of NRF1 beyond its participation in cellular antioxidant response and suggest that L-NRF1 is a negative regulator of PPARγ2 expression and thereby can suppress adipogenesis. Elsevier 2019-12-28 /pmc/articles/PMC6957832/ /pubmed/31931283 http://dx.doi.org/10.1016/j.redox.2019.101414 Text en © 2019 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Paper Xue, Peng Hou, Yongyong Zuo, Zhuo Wang, Zhendi Ren, Suping Dong, Jian Fu, Jingqi Wang, Huihui Andersen, Melvin E. Zhang, Qiang Xu, Yuanyuan Pi, Jingbo Long isoforms of NRF1 negatively regulate adipogenesis via suppression of PPARγ expression |
title | Long isoforms of NRF1 negatively regulate adipogenesis via suppression of PPARγ expression |
title_full | Long isoforms of NRF1 negatively regulate adipogenesis via suppression of PPARγ expression |
title_fullStr | Long isoforms of NRF1 negatively regulate adipogenesis via suppression of PPARγ expression |
title_full_unstemmed | Long isoforms of NRF1 negatively regulate adipogenesis via suppression of PPARγ expression |
title_short | Long isoforms of NRF1 negatively regulate adipogenesis via suppression of PPARγ expression |
title_sort | long isoforms of nrf1 negatively regulate adipogenesis via suppression of pparγ expression |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957832/ https://www.ncbi.nlm.nih.gov/pubmed/31931283 http://dx.doi.org/10.1016/j.redox.2019.101414 |
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