EPA and DHA inhibit LDL-induced upregulation of human adipose tissue NLRP3 inflammasome/IL-1β pathway and its association with diabetes risk factors

Abstract

Abstract Elevated numbers of atherogenic lipoproteins (apoB), mostly circulating as low-density lipoproteins (LDL), predict diabetes risk. We recently reported that native LDL upregulate the NLRP3 inflammasome/interleukin-1β (IL-1β) pathway in human white adipose tissue (WAT); however, nutritional approaches to target this remain unknown. We tested the hypotheses that eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids treat LDL-induced upregulation of the WAT NLRP3 inflammasome/ IL-1β-pathway and its relation to T2D risk factors in vivo and ex vivo. Forty subjects without chronic disease were enrolled into a 12-week-intervention with EPA and DHA (2.7 g/d from Webber Naturals), of whom 17 subjects with high-apoB and 16 with low-apoB completed the intervention. Supplementation with EPA and DHA abolished baseline group-differences in WAT IL-1β-secretion between subjects with high- and low-apoB. Contrary to baseline, native LDL failed to stimulate WAT IL-1β-secretion after the omega-3 intervention and rather inhibited IL-1β-secretion induced by microbial LPS. EPA and DHA also improved β-cell function and postprandial fat metabolism, in relation with their circulating levels, and blunted the association of WAT NLRP3 and IL1B mRNA expression and IL-1β-secretion with the risk factors for T2D. In line ex vivo, treatment of WAT with EPA and DHA inhibited IL-1β-secretion in a dose-dependent manner. In conclusion, supplementation with EPA and DHA treats LDL-induced upregulation of the NLRP3 inflammasome/IL-1β pathway and related metabolic anomalies, which may aid the prevention of CVD and T2D in subjects with elevated plasma apoB. ClinicalTrials.gov Identifier: NCT04496154