Abstract 18901: Calgranulins S100A8, S100A9 and S100A12 are Novel Genes Modified by n-3 PUFA Supplementation and Evoked Endotoxemia in Humans

Abstract

Introduction: We have previously identified genes involved in the adipose transcriptomic response to evoked endotoxemia in humans. Long-chain omega-3 polyunsaturated fatty acids (n-3 PUFA) may modulate chronic low-grade systemic and adipose inflammation, conferring protection in cardiometabolic disease. However, given subtle effects of n-3 PUFA in vivo, intervention studies often lack power to detect effects on resting biomarkers. We applied unbiased transcriptomics (RNASeq) to human adipose tissue in healthy individuals following supplementation with n-3 PUFA in combination with evoked endotoxemia (LPS) as a unique genomic discovery model in n-3 PUFA modulation of inflammation. Methods: Using RNASeq we analyzed transcriptomes of adipose tissue biopsies from healthy individuals at three timepoints: before and after n-3 PUFA supplementation (n=7; 3600mg/day EPA/DHA) for 6-8 weeks compared with placebo (n=6), as well as during a subsequent evoked inflammatory challenge (LPS 0.6 ng/kg I.V.). We further explored candidate gene expression in response to n-3 PUFA and LPS using human monocytes and adipocytes in vitro. Results: The transcriptomic response to LPS was altered by n-3 PUFA supplementation. We found increased up-regulation of calgranulin genes in n-3 PUFA (S100A8 16-fold, p=0.002; S100A9 8-fold, p=0.002; S100A12 32-fold, p=0.01) compared with placebo (S100A8 2-fold, p=0.003; S100A9 1.4-fold, p=0.4; S100A12 5-fold, p=0.04). These inflammasome-activating genes may be involved in atherogenesis and inflammatory diseases, and may play a role in the recruitment of inflammatory cells to adipose tissue. We found differing calgranulin gene expression in vitro in adipocytes and monocytes after n-3 PUFA (up in monocytes, down in adipocytes post DHA p<0.001) and LPS treatment (n-3 PUFA dependent decrease in monocytes, increase in adipocytes) consistent with n-3 PUFA-dependent cell-type-specific responses to inflammatory activation. Conclusions: Unbiased transcriptomics and evoked inflammation permits enhanced genomic discovery in the context of nutritional intervention. A novel mechanism of n-3 PUFA protective effects in vivo may be through modulation of expression of calgranulin genes in response to innate immune activation.