Native low-density lipoproteins are priming signals of the NLRP3 inflammasome/interleukin-1 pathway in human adipose tissue and macrophages

Elevated plasma numbers of atherogenic apoB-lipoproteins (apoB), mostly as low-density lipoproteins (LDL), predict diabetes risk by unclear mechanisms. Upregulation of the NLRP3 inflammasome/interleukin-1 beta (IL-1 beta) system in white adipose tissue (WAT) is implicated in type 2 diabetes (T2D); however, metabolic signals that stimulate it remain unexplored. We hypothesized that (1) subjects with high-apoB have higher WAT IL-1 beta-secretion than subjects with low-apoB, (2) WAT IL-1 beta-secretion is associated with T2D risk factors, and (3) LDL prime and/or activate the WAT NLRP3 inflammasome. Forty non-diabetic subjects were assessed for T2D risk factors related to systemic and WAT glucose and fat metabolism. Regulation of the NLRP3 inflammasome was explored using LDL without/with the inflammasome's priming and activation controls (LPS and ATP). LDL induced IL1B-expression and IL-1 beta-secretion in the presence of ATP in WAT and macrophages. Subjects with high-apoB had higher WAT IL-1 beta-secretion independently of covariates. The direction of association of LDL-induced WAT IL-1 beta-secretion to T2D risk factors was consistently pathological in high-apoB subjects only. Adjustment for IL-1 beta-secretion eliminated the association of plasma apoB with T2D risk factors. In conclusion, subjects with high-apoB have higher WAT IL-1 beta-secretion that may explain their risk for T2D and may be related to LDL-induced priming of the NLRP3 inflammasome.ClinicalTrials.gov (NCT04496154): Omega-3 to Reduce Diabetes Risk in Subjects With High Number of Particles That Carry "Bad Cholesterol" in the Blood-Full Text View-ClinicalTrials.gov.