Background Endoplasmic reticulum ( ER ) stress and the subsequent unfolded protein response may initially be protective, but when prolonged, have been implicated in atherogenesis in diabetic conditions. Triglycerides and free fatty acids ( FFAs ) are elevated in patients with diabetes and may contribute to ER stress. We sought to evaluate the effect of acute FFA elevation on ER stress in endothelial and circulating white cells. Methods and Results Twenty‐one healthy subjects were treated with intralipid (20%; 45 mL/h) plus heparin (12 U/kg/h) infusion for 5 hours. Along with increased triglyceride and FFA levels, intralipid/heparin infusion reduced the calf reactive hyperemic response without a change in conduit artery flow‐mediated dilation consistent with microvascular dysfunction. To investigate the short‐term effects of elevated triglycerides and FFA , we measured markers of ER stress in peripheral blood mononuclear cells ( PBMC s) and vascular endothelial cells ( VEC s). In VEC s, activating transcription factor 6 ( ATF 6) and phospho‐inositol requiring kinase 1 ( pIRE 1) proteins were elevated after infusion (both P PBMC s, ATF 6 and spliced X‐box‐binding protein 1 ( XBP ‐1) gene expression increased by 2.0‐ and 2.5‐fold, respectively (both P CHOP and GADD 34 decreased by ≈67% and 74%, respectively (both P ATF 6 and pIRE 1 protein levels also increased (both P ATF 6 after infusion, suggesting activation. Conclusions Along with microvascular dysfunction, intralipid infusion induced an early protective ER stress response evidenced by activation of ATF 6 and IRE 1 in both leukocytes and endothelial cells. Our results suggest a potential link between metabolic disturbances and ER stress that may be relevant to vascular disease.
