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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
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.
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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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