Interleukin-6 inhibits human peroxisome proliferator activated receptor alpha gene expression via CCAAT/enhancer-binding proteins in hepatocytes

Int J Biochem Cell Biol. 2007;39(10):1975-86. doi: 10.1016/j.biocel.2007.05.015. Epub 2007 May 31.

Abstract

Peroxisome proliferator activated receptor alpha has been implicated as a regulator of acute phase response genes in hepatocytes. Interleukin-6 is widely known as a major cytokine responsible in the regulation of acute phase proteins and, therefore, acute phase response. Unfortunately, to date, very little is understood about the molecular mechanisms by which interleukin-6 regulates the gene expression of peroxisome proliferator activated receptor alpha. Here, we report the molecular mechanisms by which peroxisome proliferator activated receptor alpha was regulated by interleukin-6 in human HepG2 cells. Interleukin-6 was shown to down-regulate the peroxisome proliferator activated receptor alpha gene expression at the level of gene transcription. Functional dissection of human peroxisome proliferator activated receptor alpha promoter B revealed the role of predicted CCAAT/enhancer-binding protein binding site (-164/+34) in mediating the interleukin-6 inhibitory effects on peroxisome proliferator activated receptor alpha mRNA expression and electrophoretic mobility shift assay showed the binding of CCAAT/enhancer-binding protein isoforms to this cis-acting elements was increased in interleukin-6-treated HepG2 cells. Co-transfection experiments, then, demonstrated that CCAAT/enhancer-binding protein beta either in homodimer or heterodimer with CCAAT/enhancer-binding protein alpha and CCAAT/enhancer-binding protein delta plays a predominant role in inhibiting the transcriptional activity of peroxisome proliferator activated receptor alpha promoter B, thus, reducing the peroxisome proliferator activated receptor alpha mRNA expression. These studies, therefore, suggest a novel mechanism for interleukin-6-mediated inhibition of peroxisome proliferator activated receptor alpha gene expression that involves the activation of CCAAT/enhancer-binding protein isoforms with CCAAT/enhancer-binding protein beta may play a major role.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • CCAAT-Enhancer-Binding Protein-beta / physiology
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • CCAAT-Enhancer-Binding Proteins / physiology*
  • Down-Regulation / drug effects*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism
  • Humans
  • Interleukin-6 / pharmacology*
  • PPAR alpha / genetics*
  • PPAR alpha / metabolism
  • Promoter Regions, Genetic / drug effects
  • Protein Binding / drug effects
  • Protein Isoforms / metabolism
  • Transcription, Genetic / drug effects
  • Transfection
  • Tumor Cells, Cultured

Substances

  • CCAAT-Enhancer-Binding Protein-beta
  • CCAAT-Enhancer-Binding Proteins
  • Interleukin-6
  • PPAR alpha
  • Protein Isoforms