Adipocyte-derived Lysophosphatidylcholine Activates Adipocyte and Adipose Tissue Macrophage Nod-Like Receptor Protein 3 Inflammasomes Mediating Homocysteine-Induced Insulin Resistance

EBioMedicine. 2018 May;31:202-216. doi: 10.1016/j.ebiom.2018.04.022. Epub 2018 Apr 27.

Abstract

The adipose Nod-like receptor protein 3 (NLRP3) inflammasome senses danger-associated molecular patterns (DAMPs) and initiates insulin resistance, but the mechanisms of adipose inflammasome activation remains elusive. In this study, Homocysteine (Hcy) is revealed to be a DAMP that activates adipocyte NLRP3 inflammasomes, participating in insulin resistance. Hcy-induced activation of NLRP3 inflammasomes were observed in both adipocytes and adipose tissue macrophages (ATMs) and mediated insulin resistance. Lysophosphatidylcholine (lyso-PC) acted as a second signal activator, mediating Hcy-induced adipocyte NLRP3 inflammasome activation. Hcy elevated adipocyte lyso-PC generation in a hypoxia-inducible factor 1 (HIF1)-phospholipase A2 group 16 (PLA2G16) axis-dependent manner. Lyso-PC derived from the Hcy-induced adipocyte also activated ATM NLRP3 inflammasomes in a paracrine manner. This study demonstrated that Hcy activates adipose NLRP3 inflammasomes in an adipocyte lyso-PC-dependent manner and highlights the importance of the adipocyte NLRP3 inflammasome in insulin resistance.

Keywords: Adipocyte; Adipose tissue macrophage; Homocysteine; Insulin resistance; NLRP3 inflammasome.

MeSH terms

  • Adipocytes / chemistry
  • Adipocytes / cytology
  • Adipocytes / metabolism*
  • Animals
  • Female
  • Homocysteine / pharmacology*
  • Humans
  • Inflammasomes / genetics
  • Inflammasomes / metabolism*
  • Insulin Resistance*
  • Lysophosphatidylcholines / chemistry
  • Lysophosphatidylcholines / pharmacology*
  • Macrophage Activation / drug effects*
  • Macrophages / cytology
  • Macrophages / metabolism*
  • Male
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*

Substances

  • Inflammasomes
  • Lysophosphatidylcholines
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Nlrp3 protein, mouse
  • Homocysteine