Abstract 1741: Triglyceride-mediated Leukocyte Activation: a Potential Mechanism for Atherogenesis
Introduction: Hypertriglyceridemia can lead to leukocyte activation and therefore promote atherogenesis. We studied TG-mediated leukocyte activation in vivo and in vitro.
Methods: Leukocyte activation was studied by the expression of CD11B and neutrophil(PMN)-specific CD66B during an Oral Fat Loading Test (OFLT) using flowcytometry (FACS). Incubations of freshly isolated leukocytes with chylomicrons (TRL) and lipid emulsions (ATRL) in the presence of oxidative stress scavenger DMTU were carried out. Binding of apoB to leukocytes was studied by FACS. The in vivo leukocyte uptake of TRLs was investigated by quantitating labeled dietary fatty acids in postprandial leukocytes.
Results: OFLTs (6 hrs) in 20 healthy subjects showed that monocyte CD11B increased by 32%, PMN CD11B by 68% and PMN CD66B by 24% (P<0.005 for each). PMNs co-incubated with TRLs showed 62% increased CD11B (P<0.005) but CD66B did not change. Monocytes showed a dose dependent CD11B expression by increasing concentrations of TRLs. Incubations with ATRLs showed a 5-fold increased monocyte CD11B and a dose dependent increase of PMN CD11B and CD66B. DMTU decreased only the PMN CD66B expression by 36% (P<0.05). ApoB on leukocytes from 65 different subjects measured by FACS was highest on PMNs (40.5±22.8 au) compared to monocytes (15.5±11.0 au) and lymphocytes (4.3±4.3 au) (P<0.001 by ANOVA). Postprandial experiments in 11 volunteers showed a concentration of ~2 umoles TG/L in leukocytes, which became enriched with meal-derived fatty acids ([1-13C]16:0). This was confirmed by microscopic evaluation of Sudan black-stained blood smears demonstrating intracellular fat accumulation, specifically in postprandial PMNs.
Conclusions: Acute hypertriglyceridemia is a leukocyte activator by binding of apoB-TRLs to leukocytes and uptake of fatty acids in the bloodstream associated to generation of oxidative stress. Although the total transport capacity of TRLs by leukocytes is limited, TG-mediated leukocyte activation could be an important pro-atherogenic mechanism of hypertriglyceridemia.