AMPK-independent inhibition of human macrophage ER stress response by AICAR.
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.
Collections
Subject
Macrophages
Humans
Obesity
Aminoimidazole Carboxamide
Endoribonucleases
Protein-Serine-Threonine Kinases
Membrane Transport Proteins
Equilibrative Nucleoside Transporter 1
Ribonucleotides
Cytokines
Macrophage Activation
Phosphorylation
AMP-Activated Protein Kinases
Endoplasmic Reticulum Stress
Research team
Medicinal Chemistry 2
Language
eng
Date accepted
2016-08-02
License start date
2016-08-26
Citation
Scientific reports, 2016, 6 pp. 32111 - ?
Publisher
NATURE PORTFOLIO