AMPK-independent inhibition of human macrophage ER stress response by AICAR

Sci Rep. 2016 Aug 26;6:32111. doi: 10.1038/srep32111.

Abstract

Obesity-associated insulin resistance is driven by inflammatory processes in response to metabolic overload. Obesity-associated inflammation can be recapitulated in cell culture by exposing macrophages to saturated fatty acids (SFA), and endoplasmic reticulum (ER) stress responses essentially contribute to pro-inflammatory signalling. AMP-activated protein kinase (AMPK) is a central metabolic regulator with established anti-inflammatory actions. Whether pharmacological AMPK activation suppresses SFA-induced inflammation in a human system is unclear. In a setting of hypoxia-potentiated inflammation induced by SFA palmitate, we found that the AMP-mimetic AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) potently suppressed upregulation of ER stress marker mRNAs and pro-inflammatory cytokines. Furthermore, AICAR inhibited macrophage ER stress responses triggered by ER-stressors thapsigargin or tunicamycin. Surprisingly, AICAR acted independent of AMPK or AICAR conversion to 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl monophosphate (ZMP) while requiring intracellular uptake via the equilibrative nucleoside transporter (ENT) ENT1 or the concentrative nucleoside transporter (CNT) CNT3. AICAR did not affect the initiation of the ER stress response, but inhibited the expression of major ER stress transcriptional effectors. Furthermore, AICAR inhibited autophosphorylation of the ER stress sensor inositol-requiring enzyme 1α (IRE1α), while activating its endoribonuclease activity in vitro. Our results suggest that AMPK-independent inhibition of ER stress responses contributes to anti-inflammatory and anti-diabetic effects of AICAR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Aminoimidazole Carboxamide / analogs & derivatives*
  • Aminoimidazole Carboxamide / pharmacology
  • Cytokines / metabolism
  • Endoplasmic Reticulum Stress / drug effects*
  • Endoribonucleases / metabolism
  • Equilibrative Nucleoside Transporter 1 / metabolism
  • Humans
  • Macrophage Activation / drug effects
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Membrane Transport Proteins / metabolism
  • Obesity / metabolism
  • Obesity / pathology
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / metabolism
  • Ribonucleotides / pharmacology*

Substances

  • Cytokines
  • Equilibrative Nucleoside Transporter 1
  • Membrane Transport Proteins
  • Ribonucleotides
  • SLC29A1 protein, human
  • cif nucleoside transporter
  • Aminoimidazole Carboxamide
  • ERN1 protein, human
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Endoribonucleases
  • AICA ribonucleotide