ATF3 represses PPARγ expression and inhibits adipocyte differentiation

MK Jang, MH Jung - Biochemical and biophysical research …, 2014 - Elsevier
MK Jang, MH Jung
Biochemical and biophysical research communications, 2014Elsevier
Abstract Activating transcription factor 3 (ATF3) is a stress-adaptive transcription factor that
mediates cellular stress response signaling. We previously reported that ATF3 represses
CCAAT/enhancer binding protein α (C/EBPα) expression and inhibits 3T3-L1 adipocyte
differentiation. In this study, we explored potential role of ATF3 in negatively regulating
peroxisome proliferator activated receptor-γ (PPARγ). ATF3 decreased the expression of
PPARγ and its target gene in 3T3-L1 adipocytes. ATF3 also repressed the activity of− 2.6 Kb …
Abstract
Activating transcription factor 3 (ATF3) is a stress-adaptive transcription factor that mediates cellular stress response signaling. We previously reported that ATF3 represses CCAAT/enhancer binding protein α (C/EBPα) expression and inhibits 3T3-L1 adipocyte differentiation. In this study, we explored potential role of ATF3 in negatively regulating peroxisome proliferator activated receptor-γ (PPARγ). ATF3 decreased the expression of PPARγ and its target gene in 3T3-L1 adipocytes. ATF3 also repressed the activity of −2.6 Kb promoter of mouse PPARγ2. Overexpression of PPARγ significantly prevented the ATF3-mediated inhibition of 3T3-L1 differentiation. Transfection studies with 5′ deleted-reporters showed that ATF3 repressed the activity of −2037 bp promoter, whereas it did not affect the activity of −1458 bp promoter, suggesting that ATF3 responsive element is located between the −2037 and −1458. An electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that ATF3 binds to ATF/CRE site (5′-TGACGTTT-3′) between −1537 and −1530. Mutation of the ATF/CRE site abrogated ATF3-mediated transrepression of the PPARγ2 promoter. Treatment with thapsigargin, endoplasmic reticulum (ER) stress inducer, increased ATF3 expression, whereas it decreased PPARγ expression. ATF3 knockdown significantly blocked the thapsigargin-mediated downregulation of PPARγ expression. Furthermore, overexpression of PPARγ prevented inhibition of 3T3-L1 differentiation by thapsigargin. Collectively, these results suggest that ATF3-mediated inhibition of PPARγ expression may contribute to inhibition of adipocyte differentiation during cellular stress including ER stress.
Elsevier