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Consistent with this notion, TLR2 or TLR4 knockout mice are protected from obesity-induced proinflammatory 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 proinflammatory response in vascular endothelial cells in high-lipid conditions, we compared the proinflammatory responses stimulated by palmitic acid (PA) and other canonical TLR agonists [lipopolysaccharide (LPS), Pam3-Cys-Ser-Lys4 (Pam<jats:sub>3<\/jats:sub>CSK<jats:sub>4<\/jats:sub>), or macrophage-activating lipopeptide-2)] 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 knockdown of ACSL1 blunted the PA-stimulated, but not the LPS- or Pam<jats:sub>3<\/jats:sub>CSK<jats:sub>4<\/jats:sub>-stimulated proinflammatory responses. Furthermore, triacsin C restored the insulin-stimulated vasodilation, which was impaired by PA. From the results, we concluded that PA stimulates the proinflammatory response in the vascular endothelium through an ACSL1-mediated mechanism, which is distinct from LPS- or Pam<jats:sub>3<\/jats:sub>CSK<jats:sub>4<\/jats:sub>-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. <\/jats:p>","DOI":"10.1152\/ajpendo.00117.2020","type":"journal-article","created":{"date-parts":[[2020,9,21]],"date-time":"2020-09-21T09:15:04Z","timestamp":1600679704000},"page":"E893-E903","source":"Crossref","is-referenced-by-count":21,"title":["Long-chain acyl-CoA synthetase-1 mediates the palmitic acid-induced inflammatory response in human aortic endothelial cells"],"prefix":"10.1152","volume":"319","author":[{"given":"Guang","family":"Ren","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham,  Alabama"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sushant","family":"Bhatnagar","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of 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