Palmitic acid induces guanylin gene expression through the Toll-like receptor 4/nuclear factor-κB pathway in rat macrophages

Am J Physiol Cell Physiol. 2019 Dec 1;317(6):C1239-C1246. doi: 10.1152/ajpcell.00081.2019. Epub 2019 Sep 25.

Abstract

Recently, we showed that double-transgenic rats overexpressing guanylin (Gn), a bioactive peptide, and its receptor, guanylyl cyclase-C (GC-C), specifically in macrophages demonstrate an antiobesity phenotype and low-expression levels of proinflammatory cytokines in the mesenteric fat even when fed a high-fat diet. Here, we examined the levels and mechanism of Gn and GC-C transcription following saturated fatty acid and lipopolysaccharide (LPS), an activator of Toll-like receptor 4 (TLR4), exposure by using the NR8383 macrophage cell line. In addition, the levels of guanylin and cGMP were increased by addition of either palmitic acid or LPS. Next, we investigated the interaction of the gene transcription and nuclear factor-κB (NF-κB) by using an NF-κB inhibitor and chromatin immunoprecipitation assay. We showed that palmitic acid induced Gn gene expression via TLR4 and NF-κB. Moreover, we demonstrated that NF-κB binding to the Gn promoter was responsible for the induction of gene transcription by palmitic acid or LPS. Our results indicate that saturated fatty acids such as palmitic acid activate Gn gene expression via the NF-κB pathway, raising the possibility that the activated Gn-GC-C system may contribute to the inhibition of high-fat diet-induced proinflammatory cytokines in macrophages.

Keywords: NF-κB; guanylin; guanylyl cyclase C; macrophage; palmitic acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cyclic GMP / immunology
  • Cyclic GMP / metabolism
  • Gastrointestinal Hormones / agonists
  • Gastrointestinal Hormones / genetics*
  • Gastrointestinal Hormones / immunology
  • Gene Expression Regulation
  • Genes, Reporter
  • Humans
  • Lipopolysaccharides / pharmacology*
  • Luciferases / genetics
  • Luciferases / metabolism
  • Macrophages, Alveolar / cytology
  • Macrophages, Alveolar / drug effects*
  • Macrophages, Alveolar / immunology
  • Mice
  • NF-kappa B / genetics*
  • NF-kappa B / immunology
  • Natriuretic Peptides / agonists
  • Natriuretic Peptides / genetics*
  • Natriuretic Peptides / immunology
  • Palmitic Acid / pharmacology*
  • RAW 264.7 Cells
  • Rats
  • Receptors, Guanylate Cyclase-Coupled / genetics
  • Receptors, Guanylate Cyclase-Coupled / immunology
  • Signal Transduction
  • THP-1 Cells
  • Toll-Like Receptor 4 / genetics*
  • Toll-Like Receptor 4 / immunology

Substances

  • Gastrointestinal Hormones
  • Lipopolysaccharides
  • NF-kappa B
  • Natriuretic Peptides
  • Tlr4 protein, rat
  • Toll-Like Receptor 4
  • guanylin
  • Palmitic Acid
  • Luciferases
  • Receptors, Guanylate Cyclase-Coupled
  • Cyclic GMP