ApoB-Lipoproteins Promote IL-1β Secretion from White Adipose Tissue in Humans

Abstract

The activation of the NLRP3 inflammasome and release of IL-1β are implicated in white adipose tissue (WAT) dysfunction, insulin resistance (IR) and diabetes in mice and humans. However, the metabolic signals that activate the NLRP3 inflammasome in human WAT are unclear. ApoB-lipoproteins promote WAT dysfunction and associate with inflammation and IR in obese subjects. We examined whether apoB-lipoproteins induce WAT dysfunction through activation of the NLRP3 inflammasome/IL-1β axis in vivo and ex vivo in human WAT. Plasma IL-1β levels were barely detectable (∼0.07 pg/mL) in healthy obese subjects (n=72, BMI> 27 kg/m2, >45 years). Plasma IL-1Ra, an antagonist indicating activation of the IL-1β system (∼317±332 pg/mL) correlated positively with total fat, the ratio of android/gynoid fat and plasma apoB ( reflecting the number of apoB-lipoproteins) (r=0.30) and negatively with insulin sensitivity (r=–0.35) and disposition index (r=–0.31) measured by Botnia clamp. Ex vivo: IL-1β secretion from subcutaneous WAT correlated strongly with plasma apoB (r=0.85). Treatment of subjects’ WAT with their own LDL (90% of the circulating apoB) increased IL-1β secretion by ∼121%. Ingestion of a high-fat meal increased IL-1β secretion from subjects WAT by ∼111%. Treatment of mouse macrophages with subjects’ LDL or non-apoB-lipoproteins (16 hours) had no effect on IL-1β secretion. On the other hand, VLDL, a triglyceride-rich apoB-lipoprotein that increases postprandially, increased IL-1β secretion from LPS-primed macrophages in a dose-dependent manner only with LPS. We report that apoB-lipoproteins activate the NLRP3 inflammasome/IL-1β axis in human WAT, potentially explaining higher inflammation and IR in obese subjects with hyperapoB.