The involvement of peroxisome proliferator-activated receptor gamma (PPARγ) in anti-inflammatory activity of N-stearoylethanolamine

• Published in: Heliyon Vol. 8; no. 11; p. e11336
• Main Authors: Kosiakova, H., Berdyshev, A., Dosenko, V., Drevytska, T., Herasymenko, O., Hula, N.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.11.2022; Elsevier
• Subjects: IL-1β; Inflammation; Insulin resistance; N-Stearoylethanolamine; NF-kB; PPAR; Insulin resistance; Inflammation; PPAR; IL-1β; NF-kB; N-Stearoylethanolamine
• ISSN: 2405-8440; 2405-8440
• DOI: 10.1016/j.heliyon.2022.e11336

N-stearoylethanolamine (NSE) is a bioactive lipid amine with a wide range of biological activities. Anti-inflammatory properties of NSE were previously confirmed on multiple animal models. However, the molecular mechanisms of anti-inflammatory action of NSE remain unclear. In the current study, we examined the involvement of nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) in the NF-kB –dependent pathway of anti-inflammatory action of NSE using different methodological approaches. Molecular modeling calculated the possibility of NSE binding PPAR. Ex vivo experiment, using selective agonist of PPARα/γ - LY-171883 and antagonist of PPARγ - GW9662, examined the role of PPARα/γ in the NSE’s effect on nuclear NF-kB translocation in LPS-activated rat peritoneal macrophages. Finally, the NSE’s action on mRNA level of PPARγ-dependent genes was studied in the liver of insulin-resistant rats. The results of molecular docking showed that NSE could bind to PPARγ and compete for the binding site with antagonist GW9662 and agonist LY-171883. These data was supported by in vitro study where pre-treatment with NSE prevented further LPS-induced NF-kB translocation into the nuclei of rat peritoneal macrophages. NSE treatment before GW9662 and LPS addition normalized the level of NF-kB translocation and IL-1β content. This finding confirmed a competitive binding of NSE with GW9662 for the ligand-binding domain of PPARγ. Additional in vivo study showed that NSE administration changed the mRNA expression of several PPARγ target genes, including SLC27A1 encoding fatty acid transport protein-1 and IL1RN - interleukin-1 receptor antagonist in insulin resistant rats. NSE suppressed nuclear translocation of NF-κB in LPS-stimulated peritoneal macrophages via PPARγ and changed hepatic mRNA expression of PPARγ target genes (SLC27A1, IL1RN) in insulin resistant rats. [Display omitted] N-stearoylethanolamine; PPAR; NF-kB; IL-1β; Inflammation; Insulin resistance.