Lysophosphatidylcholine promotes SREBP-2 activation via rapid cholesterol efflux and SREBP-2-independent cytokine release in human endothelial cells

J Biochem. 2015 Oct;158(4):331-8. doi: 10.1093/jb/mvv044. Epub 2015 May 21.

Abstract

Lysophosphatidylcholine (LPC) and oxysterols which are major components in oxidized low-density lipoprotein have been shown to possess an opposite effect on the expression of sterol regulatory element-binding protein-2 (SREBP-2) target genes in endothelial cells. In this study, we aimed at elucidating the mechanisms of activation of SREBP-2 by LPC and evaluating the effects of LPC and 25-hydroxycholesterol (25-HC) on the release of inflammatory cytokines. Human umbilical vein endothelial cells were treated with LPC or oxysterols including 25-HC. LPC activated SREBP-2 within 15 min, resulting in induction of expression of SREBP-2 target genes which were involved in intracellular cholesterol homeostasis. The rapid activation of SREBP-2 was caused by enhanced efflux of intracellular cholesterol, which was evaluated using (14)C-acetate. The LPC-induced activation of SREBP-2 was inhibited by addition of 25-HC. In contrast, both LPC and 25-HC increased release of interleukin-6 (IL-6) and IL-8, respectively and additively. In conclusion, LPC activated SREBP-2 via enhancement of cholesterol efflux, which was suppressed by 25-HC. The release of inflammatory cytokines such as IL-6 and IL-8 in endothelial cells was SREBP-2-independent. LPC and 25-HC may act competitively in cholesterol homeostasis but additively in inflammatory cytokine release.

Keywords: 25-hydroxycholesterol; SREBP; cholesterol; cytokine; lysophosphatidylcholine.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Atherosclerosis / blood
  • Atherosclerosis / immunology
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Biological Transport
  • Carbon Radioisotopes
  • Cell Membrane / immunology
  • Cell Membrane / metabolism
  • Cell Membrane / pathology
  • Cell Nucleus / immunology
  • Cell Nucleus / metabolism
  • Cell Nucleus / pathology
  • Cells, Cultured
  • Cholesterol / blood
  • Cholesterol / chemistry
  • Cholesterol / metabolism*
  • Down-Regulation
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / immunology
  • Endothelium, Vascular / metabolism*
  • Human Umbilical Vein Endothelial Cells / cytology
  • Human Umbilical Vein Endothelial Cells / immunology
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Hydroxycholesterols / analysis
  • Hydroxycholesterols / blood
  • Hydroxycholesterols / metabolism
  • Interleukin-6 / agonists
  • Interleukin-6 / blood
  • Interleukin-6 / metabolism*
  • Interleukin-8 / agonists
  • Interleukin-8 / blood
  • Interleukin-8 / metabolism*
  • Lipoproteins, LDL / blood
  • Lipoproteins, LDL / chemistry
  • Lipoproteins, LDL / metabolism
  • Lysophosphatidylcholines / analysis
  • Lysophosphatidylcholines / antagonists & inhibitors
  • Lysophosphatidylcholines / blood
  • Lysophosphatidylcholines / metabolism*
  • Oxidation-Reduction
  • Sterol Regulatory Element Binding Protein 2 / agonists*
  • Sterol Regulatory Element Binding Protein 2 / antagonists & inhibitors
  • Sterol Regulatory Element Binding Protein 2 / genetics
  • Sterol Regulatory Element Binding Protein 2 / metabolism
  • Up-Regulation*

Substances

  • CXCL8 protein, human
  • Carbon Radioisotopes
  • Hydroxycholesterols
  • IL6 protein, human
  • Interleukin-6
  • Interleukin-8
  • Lipoproteins, LDL
  • Lysophosphatidylcholines
  • SREBF2 protein, human
  • Sterol Regulatory Element Binding Protein 2
  • oxidized low density lipoprotein
  • 25-hydroxycholesterol
  • Cholesterol