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Negative Regulation of DsbA-L Gene Expression by the Transcription Factor Sp1

Disulfide-bond A oxidoreductase-like protein (DsbA-L) possesses beneficial effects such as promoting adiponectin multimerization and stability, increasing insulin sensitivity, and enhancing energy metabolism. The expression level of DsbA-L is negatively correlated with obesity in mice and humans, bu...

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Autores principales: Fang, Qichen, Yang, Wenjing, Li, Huating, Hu, Wenxiu, Chen, Lihui, Jiang, Shan, Dong, Kun, Song, Qianqian, Wang, Chen, Chen, Shuo, Liu, Feng, Jia, Weiping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237990/
https://www.ncbi.nlm.nih.gov/pubmed/25024375
http://dx.doi.org/10.2337/db14-0182
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author Fang, Qichen
Yang, Wenjing
Li, Huating
Hu, Wenxiu
Chen, Lihui
Jiang, Shan
Dong, Kun
Song, Qianqian
Wang, Chen
Chen, Shuo
Liu, Feng
Jia, Weiping
author_facet Fang, Qichen
Yang, Wenjing
Li, Huating
Hu, Wenxiu
Chen, Lihui
Jiang, Shan
Dong, Kun
Song, Qianqian
Wang, Chen
Chen, Shuo
Liu, Feng
Jia, Weiping
author_sort Fang, Qichen
collection PubMed
description Disulfide-bond A oxidoreductase-like protein (DsbA-L) possesses beneficial effects such as promoting adiponectin multimerization and stability, increasing insulin sensitivity, and enhancing energy metabolism. The expression level of DsbA-L is negatively correlated with obesity in mice and humans, but the underlying mechanisms remain unknown. To address this question, we generated reporter gene constructs containing the promoter sequence of the mouse DsbA-L gene. Deletion analysis showed that the proximal promoter of mouse DsbA-L is located between −186 and −34 bp relative to the transcription start site. In silico analysis identified a putative Sp1 transcription factor binding site in the first intron of the DsbA-L gene. Electrophoretic mobility shift assay and chromatin immunoprecipitation analysis indicated that Sp1 bound to this intron region in vitro and in intact cells. Overexpression of Sp1 or suppressing Sp1 expression by siRNA reduced or increased DsbA-L promoter activity, respectively. The binding activity of Sp1 was gradually decreased during 3T3-L1 cell differentiation and was significantly increased in adipose tissues of obese mice. Our results identify Sp1 as an inhibitor of DsbA-L gene transcription, and the Sp1-mediated inhibition of DsbA-L gene expression may provide a mechanism underlying obesity-induced adiponectin downregulation and insulin resistance.
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spelling pubmed-42379902015-12-01 Negative Regulation of DsbA-L Gene Expression by the Transcription Factor Sp1 Fang, Qichen Yang, Wenjing Li, Huating Hu, Wenxiu Chen, Lihui Jiang, Shan Dong, Kun Song, Qianqian Wang, Chen Chen, Shuo Liu, Feng Jia, Weiping Diabetes Obesity Studies Disulfide-bond A oxidoreductase-like protein (DsbA-L) possesses beneficial effects such as promoting adiponectin multimerization and stability, increasing insulin sensitivity, and enhancing energy metabolism. The expression level of DsbA-L is negatively correlated with obesity in mice and humans, but the underlying mechanisms remain unknown. To address this question, we generated reporter gene constructs containing the promoter sequence of the mouse DsbA-L gene. Deletion analysis showed that the proximal promoter of mouse DsbA-L is located between −186 and −34 bp relative to the transcription start site. In silico analysis identified a putative Sp1 transcription factor binding site in the first intron of the DsbA-L gene. Electrophoretic mobility shift assay and chromatin immunoprecipitation analysis indicated that Sp1 bound to this intron region in vitro and in intact cells. Overexpression of Sp1 or suppressing Sp1 expression by siRNA reduced or increased DsbA-L promoter activity, respectively. The binding activity of Sp1 was gradually decreased during 3T3-L1 cell differentiation and was significantly increased in adipose tissues of obese mice. Our results identify Sp1 as an inhibitor of DsbA-L gene transcription, and the Sp1-mediated inhibition of DsbA-L gene expression may provide a mechanism underlying obesity-induced adiponectin downregulation and insulin resistance. American Diabetes Association 2014-12 2014-11-13 /pmc/articles/PMC4237990/ /pubmed/25024375 http://dx.doi.org/10.2337/db14-0182 Text en © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
spellingShingle Obesity Studies
Fang, Qichen
Yang, Wenjing
Li, Huating
Hu, Wenxiu
Chen, Lihui
Jiang, Shan
Dong, Kun
Song, Qianqian
Wang, Chen
Chen, Shuo
Liu, Feng
Jia, Weiping
Negative Regulation of DsbA-L Gene Expression by the Transcription Factor Sp1
title Negative Regulation of DsbA-L Gene Expression by the Transcription Factor Sp1
title_full Negative Regulation of DsbA-L Gene Expression by the Transcription Factor Sp1
title_fullStr Negative Regulation of DsbA-L Gene Expression by the Transcription Factor Sp1
title_full_unstemmed Negative Regulation of DsbA-L Gene Expression by the Transcription Factor Sp1
title_short Negative Regulation of DsbA-L Gene Expression by the Transcription Factor Sp1
title_sort negative regulation of dsba-l gene expression by the transcription factor sp1
topic Obesity Studies
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237990/
https://www.ncbi.nlm.nih.gov/pubmed/25024375
http://dx.doi.org/10.2337/db14-0182
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