NLRP3 inflammasome mediate palmitate-induced endothelial dysfunction

Aims: Free fatty acids (FFA) is a key contributor to insulin resistance and endothelial dysfunction. However, the precise mechanism underlying the role of FFA remains elusive. This study aimed to investigate the role of NLRP3 (NOD-like receptor pyrin domain containing-3) inflammasome in FFA induced endothelial dysfunction. Main methods: HUVECs were transfected with NLRP3 siRNA and then stimulated with LPS and palmitate. C57 BL/6 J mice transfected with NLRP3 Lenti-Virus were fed with a high-fat diet (HFD). The levels of NLRP3 inflammasome, AMPK alpha (AMP-activated protein kinase), endothelial nitric oxide synthase (eNOS) and the activity of the insulin signal pathway, in endothelial cells were determined via Western blotting. Endothelial function was determined by measuring the level of endothelium-dependent vasodilatation. Key findings: FFA could activate NLRP3 inflammasome and induce IL-1 beta release both in vitro. and in vivo. Using siRNA and Lenti-Virus to inhibit NLRP3 abolished palmitate-induced IL-1 beta release and restored impaired phosphorylation of IRS-1 (Tyr), Akt (Ser473) and eNOS (Ser1177) and ACh-mediated endothelium-dependent vasorelaxation induced by palmitate. AMPK alpha activator AICAR(5-aminoimidazole-4-carbox-amide-1-beta-d-ribofuranoside) inhibited NLRP3 inflammasome activation and decreased IL-1 beta release and restored impaired insulin signal pathway induced by palmitate. Significance: NLRP3 inflammasome activation via AMPK alpha inactivation mediated palmitate-induced endothelial dysfunction through involves IL-1 beta-induced insulin signal pathway.