Inflammation-induced nitric oxide suppresses PPARα expression and function via downregulation of Sp1 transcriptional activity in adipocytes

• Published in: Biochimica et biophysica acta. Gene regulatory mechanisms 2023-12, Vol.1866 (4), p.194987-194987, Article 194987
• Main Authors: Kwon, Jungin, Aoki, Yumeko, Takahashi, Haruya, Nakata, Rieko, Kawarasaki, Satoko, Ni, Zheng, Yu, Rina, Inoue, Hiroyasu, Inoue, Kazuo, Kawada, Teruo, Goto, Tsuyoshi
• Format: Article
• Language: English
• Subjects: Adipocytes - metabolism; Adipose tissue; Animals; Down-Regulation; Endoplasmic reticulum stress; Inflammation; Inflammation - genetics; Mice; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide - pharmacology; Obesity; PPAR alpha - genetics; PPAR alpha - metabolism; PPARα; Sp1
• ISSN: 1874-9399; 1876-4320
• DOI: 10.1016/j.bbagrm.2023.194987

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. •Inflammation-induced NO suppresses Ppara expression in adipocytes.•ER stress mediates the suppressive effects of NO on Ppara expression in adipocytes.•NO suppresses Ppara expression by reducing its promoter activity.•NO reduces the occupancy of Sp1 in the proximal region of the Ppara promoter.•Downregulated Ppara expression in WAT of db/db mice were restored by a NOS2 inhibitor.