1141-P: Short-Chain Fatty Acid Acetate Increases TNF-a-Induced MCP-1 Production in Monocytes via the ACSL-1/MAPK/NF-?B Axis: Significance for Inflammation and Insulin Resistance

Short-chain fatty acids (SCFAs) are formed as by-products of dietary fiber metabolism by gut bacteria and have multiple immunomodulatory functions in different cells involved in the inflammatory and immune responses. In general, the anti-inflammatory role of SCFAs is well documented. Here, we investigated whether SCFAs could modulate the TNF-α-mediated induction of chemokine MCP-1 (also known as CCL2) in monocytes/macrophages; and if so, which mechanisms were involved. Monocytic cells were exposed to SCFAs including acetate, propionate, and butyrate, with or without TNF-α, and the release of MCP-1 was measured. We found that none of the SCFAs suppressed TNF-α-induced MCP-1 release in monocytes. However, challenge with acetate in combination with TNF-α resulted in substantially greater MCP-1 release from monocytic cells than challenge with TNF-α alone, indicating synergistic effects. Interestingly, such effects of acetate were not seen in macrophages. Synergistic upregulation of MCP-1 was mediated through the activation of acyl-CoA synthetase 1 (ACSL1). Acetate/TNFα induced phosphorylation of p38, ERK1/2, and NF-κB was observed during the secretion of MCP-1. Acetate/TNF-α mediated synergistic expression of MCP-1 was significantly reduced by the inhibition of p38 MAPK, ERK1/2 and NF-κB signaling pathways. Furthermore, inhibition of the ACSL1 activity also attenuates the TNF-α-mediated phosphorylation of p38 MAPK, ERK1/2, and NF-κB. ACSL1 inhibition led to a lower induction of NF-κB/AP-1 activity in response to co-stimulation with acetate and TNF-α. In conclusion, these data support the proinflammatory, rather than anti-inflammatory, effects of acetate on TNF-α-mediated MCP-1 expression in monocytes involving the ACSL1/MAPK/NF-kB axis. These findings point to the differential effects of SCFA acetate in the settings of obesity and metabolic inflammation/insulin resistance. Disclosure R. Ahmad: None. A. Abu alroub: None. F. Alrashed: None. A. Al-sayyar: None. N. Akhter: None. S. P. Kochumon: None. F. Almulla: None. S. T. Sindhu: None.