Inflammation-induced nitric oxide suppresses PPARα expression and function via downregulation of Sp1 transcriptional activity in adipocytes
Copyright © 2023 Elsevier B.V. All rights reserved..
The activation of peroxisome proliferator-activated receptor alpha (PPARα), a ligand-dependent transcription factor that regulates lipid oxidation-related genes, has been employed to treat hyperlipidemia. Emerging evidence indicates that Ppara gene expression decreases in adipose tissue under obese conditions; however, the underlying molecular mechanisms remain elusive. Here, we demonstrate that nitric oxide (NO) suppresses Ppara expression by regulating its promoter activity via suppression of specificity protein 1 (Sp1) transcriptional activity in adipocytes. NO derived from lipopolysaccharide (LPS) -activated macrophages or a NO donor (NOR5) treatment, suppressed Ppara mRNA expression in 10T1/2 adipocytes. In addition, Ppara transcript levels were reduced in the white adipose tissue (WAT) in both acute and chronic inflammation mouse models; however, such suppressive effects were attenuated via a nitric oxide synthase 2 (NOS2) inhibitor. Endoplasmic reticulum (ER) stress inhibitors attenuated the NO-induced repressive effects on Ppara gene expression in 10T1/2 adipocytes. Promoter mutagenesis and chromatin immunoprecipitation assays revealed that NO decreased the Sp1 occupancy in the proximal promoter regions of the Ppara gene, which might partially result from the reduced Sp1 expression levels by NO. This study delineated the molecular mechanism that modulates Ppara gene transcription upon NO stimulation in white adipocytes, suggesting a possible mechanism for the transcriptional downregulation of Ppara in WAT under obese conditions.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:1866 |
|---|---|
| Enthalten in: |
Biochimica et biophysica acta. Gene regulatory mechanisms - 1866(2023), 4 vom: 15. Dez., Seite 194987 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Kwon, Jungin [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
31C4KY9ESH |
|---|
| Anmerkungen: |
Date Completed 20.11.2023 Date Revised 29.12.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.bbagrm.2023.194987 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM362357315 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM362357315 | ||
| 003 | DE-627 | ||
| 005 | 20240108135922.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.bbagrm.2023.194987 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1242.xml |
| 035 | |a (DE-627)NLM362357315 | ||
| 035 | |a (NLM)37739218 | ||
| 035 | |a (PII)S1874-9399(23)00082-2 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Kwon, Jungin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Inflammation-induced nitric oxide suppresses PPARα expression and function via downregulation of Sp1 transcriptional activity in adipocytes |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 20.11.2023 | ||
| 500 | |a Date Revised 29.12.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier B.V. All rights reserved. | ||
| 520 | |a The activation of peroxisome proliferator-activated receptor alpha (PPARα), a ligand-dependent transcription factor that regulates lipid oxidation-related genes, has been employed to treat hyperlipidemia. Emerging evidence indicates that Ppara gene expression decreases in adipose tissue under obese conditions; however, the underlying molecular mechanisms remain elusive. Here, we demonstrate that nitric oxide (NO) suppresses Ppara expression by regulating its promoter activity via suppression of specificity protein 1 (Sp1) transcriptional activity in adipocytes. NO derived from lipopolysaccharide (LPS) -activated macrophages or a NO donor (NOR5) treatment, suppressed Ppara mRNA expression in 10T1/2 adipocytes. In addition, Ppara transcript levels were reduced in the white adipose tissue (WAT) in both acute and chronic inflammation mouse models; however, such suppressive effects were attenuated via a nitric oxide synthase 2 (NOS2) inhibitor. Endoplasmic reticulum (ER) stress inhibitors attenuated the NO-induced repressive effects on Ppara gene expression in 10T1/2 adipocytes. Promoter mutagenesis and chromatin immunoprecipitation assays revealed that NO decreased the Sp1 occupancy in the proximal promoter regions of the Ppara gene, which might partially result from the reduced Sp1 expression levels by NO. This study delineated the molecular mechanism that modulates Ppara gene transcription upon NO stimulation in white adipocytes, suggesting a possible mechanism for the transcriptional downregulation of Ppara in WAT under obese conditions | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Adipose tissue | |
| 650 | 4 | |a Endoplasmic reticulum stress | |
| 650 | 4 | |a Inflammation | |
| 650 | 4 | |a Nitric oxide | |
| 650 | 4 | |a PPARα | |
| 650 | 4 | |a Sp1 | |
| 650 | 7 | |a PPAR alpha |2 NLM | |
| 650 | 7 | |a Nitric Oxide |2 NLM | |
| 650 | 7 | |a 31C4KY9ESH |2 NLM | |
| 700 | 1 | |a Aoki, Yumeko |e verfasserin |4 aut | |
| 700 | 1 | |a Takahashi, Haruya |e verfasserin |4 aut | |
| 700 | 1 | |a Nakata, Rieko |e verfasserin |4 aut | |
| 700 | 1 | |a Kawarasaki, Satoko |e verfasserin |4 aut | |
| 700 | 1 | |a Ni, Zheng |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Rina |e verfasserin |4 aut | |
| 700 | 1 | |a Inoue, Hiroyasu |e verfasserin |4 aut | |
| 700 | 1 | |a Inoue, Kazuo |e verfasserin |4 aut | |
| 700 | 1 | |a Kawada, Teruo |e verfasserin |4 aut | |
| 700 | 1 | |a Goto, Tsuyoshi |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Biochimica et biophysica acta. Gene regulatory mechanisms |d 2017 |g 1866(2023), 4 vom: 15. Dez., Seite 194987 |w (DE-627)NLM260119539 |x 1876-4320 |7 nnns |
| 773 | 1 | 8 | |g volume:1866 |g year:2023 |g number:4 |g day:15 |g month:12 |g pages:194987 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.bbagrm.2023.194987 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 1866 |j 2023 |e 4 |b 15 |c 12 |h 194987 | ||