Long-chain acyl-CoA synthetase 1 mediates the palmitic acid-induced inflammatory response in human aortic endothelial cells

Saturated fatty acid (SFA) induces pro-inflammatory response through a toll-like receptor (TLR)-mediated mechanism, which is associated with cardiometabolic diseases such as obesity, insulin resistance, and endothelial dysfunction. Consistent with this notion, TLR2 or TLR4 knock-out mice are protected from obesity-induced pro-inflammatory response and endothelial dysfunction. Although SFA causes endothelial dysfunction through TLR-mediated signaling pathways, the mechanisms underlying SFA-stimulated inflammatory response are not completely understood. To understand the pro-inflammatory response in vascular endothelial cells in high lipid conditions, we compared the pro-inflammatory responses stimulated by palmitic acid (PA) and other canonical TLR agonists (LPS, Pam₃CSK_4, orMALP2) in human aortic endothelial cells. The expression profiles of E-selectin and the signal transduction pathways stimulated by PA were distinct from those stimulated by canonical TLR agonists. Inhibition of long-chain acyl-CoA synthetases (ACSL) by a pharmacological inhibitor or knock-down of ACSL1 blunted the PA-stimulated, but not the LPS- or Pam₃CSK₄-stimulated pro-inflammatory responses. Furthermore, triacsin C restored the insulin-stimulated vasodilation, which was impaired by PA. From the results, we concluded that PA stimulates the pro-inflammatory response in the vascular endothelium through an ACSL1-mediated mechanism, which is distinct from LPS- or Pam3CSK4-stimulated responses. The results suggest that endothelial dysfunction caused by PA may require to undergo intracellular metabolism. This expands the understanding of the mechanisms by which TLRs mediate inflammatory responses in endothelial dysfunction and cardiovascular disease.

Keywords: Acyl-CoA synthetase; Endothelial function; Inflammation; Palmitic acid; Saturated fatty acid.